Dihydrobenzofuranyl Alkanamine Derivatives and Methods for Using Same

ABSTRACT

Compounds of Formula 1 or pharmaceutically acceptable salts thereof are provided: 
     
       
         
         
             
             
         
       
     
     which are agonists or partial agonists of the 2C subtype of brain serotonin receptors. The compounds, and compositions containing the compounds, can be used to treat a variety of central nervous system disorders such as schizophrenia.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention claims priority benefit of U.S. Provisional Application Ser. No. 60/514,454, filed Oct. 24, 2003, which is incorporated herein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to novel 1-(2,3-dihydro-1-benzofuran-2-yl)alkanamine derivatives that act as agonists and partial agonists of the 5-HT_(2C) receptor, processes for their preparation, and their use in medicine.

BACKGROUND OF THE INVENTION

Schizophrenia affects approximately 5 million people. The most prevalent treatments for schizophrenia are currently the ‘atypical’ antipsychotics, which combine dopamine (D₂) and serotonin (5-HT_(2A)) receptor antagonism. Despite the reported improvements in efficacy and side-effect liability of atypical antipsychotics relative to typical antipsychotics, these compounds do not appear to adequately treat all the symptoms of schizophrenia and are accompanied by problematic side effects, such as weight gain (Allison, D. B., et. al., Am. J. Psychiatry, 156: 1686-1696, 1999; Masand, P. S., Exp. Opin. Pharmacother. I: 377-389, 2000; Whitaker, R., Spectrum Life Sciences. Decision Resources. 2:1-9, 2000).

Atypical antipsychotics also bind with high affinity to 5-HT_(2C) receptors and function as 5-HT_(2C) receptor antagonists or inverse agonists. Weight gain is a problematic side effect associated with atypical antipsychotics such as clozapine and olanzapine, and it has been suggested that 5-HT_(2C) antagonism is responsible for the increased weight gain. Conversely, stimulation of the 5-HT_(2C) receptor is known to result in decreased food intake and body weight (Walsh et. al., Psychopharmacology 124: 57-73, 1996; Cowen, P. J., et. al., Human Psychopharmacology 10: 385-391, 1995; Rosenzweig-Lipson, S., et. al., ASPET abstract, 2000).

Several lines of evidence support a role for 5-HT_(2C) receptor agonism or partial agonism as a treatment for schizophrenia. Studies suggest that 5-HT_(2C) antagonists increase synaptic levels of dopamine and may be effective in animal models of Parkinson's disease (Di Matteo, V., et. al., Neuropharmacology 37: 265-272, 1998; Fox, S. H., et. al., Experimental Neurology 151: 35-49, 1998). Since the positive symptoms of schizophrenia are associated with increased levels of dopamine, compounds with actions opposite to those of 5-HT_(2C) antagonists, such as 5-HT_(2C) agonists and partial agonists, should reduce levels of synaptic dopamine. Recent studies have demonstrated that 5-HT_(2C) agonists decrease levels of dopamine in the prefrontal cortex and nucleus accumbens (Millan, M. J., et. al., Neuropharmacology 37: 953-955, 1998; Di Matteo, V., et. al., Neuropharmacology 38: 1195-1205, 1999; Di Giovanni, G., et. al., Synapse 35: 53-61, 2000), brain regions that are thought to mediate critical antipsychotic effects of drugs like clozapine. However, 5-HT_(2C) agonists do not decrease dopamine levels in the striatum, the brain region most closely associated with extrapyramidal side effects. In addition, a recent study demonstrates that 5-HT_(2C) agonists decrease firing in the ventral tegmental area (VTA), but not in the substantia nigra. The differential effects of 5-HT_(2C) agonists in the mesolimbic pathway relative to the nigrostriatal pathway suggest that 5-HT_(2C) agonists have limbic selectivity, and will be less likely to produce extrapyramidal side effects associated with typical antipsychotics.

SUMMARY OF THE INVENTION

The present invention relates to certain dihydrobenzofuranyl alkanamine derivatives and to their use in medicine. In one aspect, the invention relates to novel 1-(2,3-dihydro-1-benzofuran-2-yl)alkanamine derivatives that act as agonists or partial agonists of the 5-HT_(2C) receptor. The compounds can be used, for example, to treat schizophrenia and the concomitant mood disorders and cognitive impairments of schizophrenia. Compounds of the present invention are preferably less likely to produce the body weight increases associated with current atypical antipsychotics. The compounds of the present invention can also be used for the treatment of obesity and its comorbidities.

In certain embodiments, the invention relates to compounds of Formula 1:

or pharmaceutically acceptable salts thereof; wherein:

R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring;

alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen;

R¹ and R² are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms;

R^(3a) and R^(3b) are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms;

R⁴, R⁵, R⁶, and R⁷ are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and

n is 1, 2 or 3;

wherein at least one of R⁴, R⁵, R⁶ and R⁷ is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R⁸, wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R⁸ is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and

wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms.

In certain other embodiments, the invention relates to methods for treating a patient suffering from schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, L-DOPA-induced psychosis, psychosis associated with Alzheimer's dementia, psychosis associated with Parkinson's disease, psychosis associated with Lewy body disease, dementia, memory deficit, intellectual deficit associated with Alzheimer's disease, bipolar disorders, depressive disorders, mood episodes, anxiety disorders, adjustment disorders, eating disorders, epilepsy, sleep disorders, migraines, sexual dysfunction, substance abuse, addiction to alcohol and various other drugs, including cocaine and nicotine, gastrointestinal disorders, obesity, or a central nervous system deficiency associated with trauma, stroke, or spinal cord injury that includes administering to the patient a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof.

In still other embodiments, the invention relates to compositions comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel 1-(2,3-dihydro-1-benzofuran-2-yl)alkanamine derivatives that are agonists or partial agonists of the 2c subtype of brain serotonin receptors.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbon chain having up to 8 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. The term “alkyl” includes, but is not limited to, straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl. In some embodiments, the alkyl group is preferably branched having 3 to 8 carbon atoms. The term “lower alkyl” refers to an alkyl group having 1 to 3 carbon atoms.

The term “alkenyl,” as used herein refers to an aliphatic straight or branched hydrocarbon chain having 2 to 8 carbon atoms that may contain 1 to 3 double bonds. Examples of alkenyl groups include vinyl, prop-1-enyl, allyl, methallyl, but-1-enyl, but-2-enyl, but-3-enyl, or 3,3-dimethylbut-1-enyl. In some embodiments, the alkenyl is preferably a branched alkenyl of 3 to 8 carbon atoms. The term “lower alkenyl” refers to an alkenyl group having 1 to 3 carbon atoms.

The term “cycloalkyl,” as used herein, refers to a saturated or partially saturated, hydrocarbon ring containing 3 to 8 carbon atoms and more preferably 5 to 7 carbon atoms. Cycloalkyl groups may be monocyclic or bicyclic, and more preferably monocyclic. Bicyclic cycloalkyl groups are preferably bridged. “Bridged” refers to a cycloalkyl group that contains at least one carbon-carbon bond between two non-adjacent carbon atoms of the cycloalkyl ring. “Partially saturated” refers to a nonaromatic cycloalkyl group containing at least one double bond and preferably one double bond. Preferably, the cycloalkyl group is saturated. The cycloalkyl group may be unsubstituted or substituted as described hereinafter. The term “alkylcycloalkyl,” as used herein, refers to the group —R-cycloalkyl, where cycloalkyl is as defined above and R is an alkyl moiety having 1 to 6, preferably 1 to 4, and more preferably 1 to 3 carbon atoms.

The term “heterocycloalkyl,” as used herein, refers to a 3 to 8 membered, and more preferably 5 to 7 membered cycloalkyl group in which one to three carbon atoms of the cycloalkyl group are replaced with a heteroatom independently selected from oxygen, nitrogen, or sulfur. The heterocycloalkyl group may be saturated or partially saturated, and may be monocyclic or bicyclic (such as bridged). Preferably, the heterocycloalkyl is monocyclic. The heterocycloalkyl group may be unsubstituted or substituted as described hereinafter.

The term “aryl,” as used herein refers to a 5 to 10 membered carbocyclic aromatic ring. The aryl may be monocyclic or bicyclic, and may be substituted or unsubstituted. Monocyclic aryl groups preferably have 5, 6, or 7 members and bicyclic aryl groups preferably have 8, 9 or 10 members. Exemplary aryl groups include phenyl and naphthyl.

The term “aryloxy,” as used herein, refers to the group Ar—O—, where Ar is an aryl group of 5 to 10 carbon atoms as previously described.

The term “heteroaryl,” as used herein, refers to a 5 to 10 membered monocyclic or bicyclic carbon containing aromatic ring having 1 to 3 of its ring members independently selected from nitrogen, sulfur or oxygen. Monocyclic rings preferably have 5 to 6 members and bicyclic rings preferably have 8 to 10 membered ring structures. The heteroaryl group may be unsubstituted or substituted as described hereinafter. Examples of heteroaryls include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, or quinazolinyl.

The term “perfluoroalkyl,” as used herein, refers to a straight or branched aliphatic hydrocarbon chain of 1 to 6 carbon atoms and preferably 1 to 3 carbon atoms, in which all hydrogens are replaced with fluorine.

The term “alkanamido,” as used herein, refers to the group R—C(═O)—NH— where R is an alkyl group of 1 to 5 carbon atoms.

The term “alkanoyl,” as used herein, refers to the group R—C(═O)— where R is an alkyl group of 1 to 5 carbon atoms.

The term “alkanoyloxy,” as used herein, refers to the group R—C(═O)—O— where R is an alkyl group of 1 to 5 carbon atoms.

The term “alkanesulfonamido,” as used herein, refers to the group R—S(O)₂—NH— where R is an alkyl group of 1 to 6 carbon atoms.

The term “alkoxy,” as used herein, refers to the group R—O— where R is an alkyl group of 1 to 6 carbon atoms.

The term “perfluoroalkoxy,” as used herein, refers to the group R—O where R is a perfluoroalkyl group of 1 to 6 carbon atoms.

The terms “monoalkylamino” and “dialkylamino,” as used herein, respectively refer to —NHR and —NRR_(a), where R and R_(a) are independently selected from an alkyl group of 1 to 6 carbon atoms.

The term “carboxamido,” as used herein, refers to the group NH₂—C(═O)—.

The term “carboalkoxy,” as used herein, refers to the group R—O—C(═O)— where R is an alkyl group of 1 to 5 carbon atoms.

The term “carboxy,” as used herein, refers to the group —COOH.

The terms “halogen” or “halo,” as used herein, refer to chlorine, bromine, fluorine or iodine.

The term “substituted,” as used herein, refers to a moiety, such as an aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety having from 1 to about 5 substituents, and more preferably from 1 to about 3 substituents independently selected from a halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms. Preferred substituents are a halogen atom, a lower alkyl, a perfluoroalkyl of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms or a perfluoroalkoxy of 1 to 3 carbon atoms.

The terms “effective amount” and “therapeutically effective amount,” as used herein, refer to the amount of a compound of Formula 1 that, when administered to a patient, is effective to at least partially treat a condition from which the patient is suffering from. Such conditions include, but are not limited to, schizophrenia, schizoaffective disorder, schizophreniform disorder, L-DOPA-induced psychosis, bipolar disorder, obesity, obsessive compulsive disorder, depression, panic disorder, sleep disorders, eating disorders, and epilepsy.

The term “pharmaceutically acceptable salts” or “pharmaceutically acceptable salt” refers to salts derived from treating a compound of Formula 1 with an organic or inorganic acid such as, for example, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, or similarly known acceptable acids.

The term “patient,” as used herein, refers to a mammal.

The terms “administer,” “administering,” or “administration,” as used herein, refer to either directly administering a compound or composition to a patient, or administering a prodrug derivative or analog of the compound to the patient, which will form an equivalent amount of the active compound or substance within the patient's body.

The terms “treat” or “treating,” as used herein, refers to partially or completely alleviating, inhibiting, preventing, ameliorating and/or relieving the condition.

The terms “suffer” or “suffering” as used herein refers to one or more conditions that a patient has been diagnosed with, or is suspected to have.

In certain embodiments, the invention relates to compounds of Formula 1:

or pharmaceutically acceptable salts thereof; wherein:

R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring;

alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen;

R¹ and R² are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms;

R^(3a) and R^(3b) are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms;

R⁴, R⁵, R⁶, and R⁷ are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and

n is 1, 2 or 3;

wherein at least one of R⁴, R⁵, R⁶ and R⁷ is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R⁸, wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R⁸ is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and

wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms.

As set forth above, R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring. Alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen. In some embodiments, R, R′, R¹, and R² are each, independently, hydrogen or alkyl of 1 to 6 carbon atoms. In certain embodiments, R′ is hydrogen, and R, R¹, and R² are each independently hydrogen or alkyl of 1 to 6 carbon atoms. In certain preferred embodiments, each of R, R′, R¹, and R² is hydrogen.

As also set forth above, R^(3a) and R^(3b) may each be selected, independently, from hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms. In certain embodiments, R^(3a) and R^(3b) are each independently hydrogen or alkyl of 1 to 3 carbon atoms and more preferably hydrogen.

R⁴, R⁵, R⁶, and R⁷ may each be selected, independently, from hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, and 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated. Moreover, at least one of R⁴, R⁵, R⁶ and R⁷ is —Y—R⁸, wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH, and R⁸ is an aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, 3 to 8 membered heterocycloalkyl, branched alkyl of 3 to 8 carbon atoms, or branched alkenyl of 3 to 8 carbon atoms. Additionally, where any of R⁴, R⁵, R⁶, and R⁷ is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, it may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms.

In certain preferred embodiments, Y is a direct bond.

In certain embodiments, R⁴, R⁵, R⁶, and R⁷ are preferably selected from hydrogen, halogen, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, alkenyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, 3 to 8 membered heterocycloalkyl, aryl of 5 to 10 carbon atoms, or 5 to 10 membered heteroaryl, provided that at least one of R⁴, R⁵, R⁶ and R⁷ is an aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, 3 to 8 membered heterocycloalkyl, branched alkyl of 3 to 8 carbon atoms, or branched alkenyl of 3 to 8 carbon atoms, wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms. Preferably, at least one of R⁴, R⁵, R⁶ and R⁷ and more preferably at least one of R⁴, R⁵ and R⁷ is an aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl.

In certain preferred embodiments of the invention, R⁴, R⁵, and R⁶ are, independently, hydrogen, halogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, perfluoroalkyl of 1 to 3 carbon atoms, or perfluoroalkoxy of 1 to 3 carbon atoms, and R⁷ is a branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, 3 to 8 membered heterocycloalkyl, aryl of 5 to 10 carbon atoms, or 5 to 10 membered heteroaryl, wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms. More preferably, R⁷ is a branched alkyl of 3 to 6 carbon atoms, branched alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl of 5 to 10 carbon atoms, or 5 to 10 membered heteroaryl, each of which may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms.

In other preferred embodiments of the invention, each of R⁴, R⁵ and R⁷ is, independently, aryl of 5 to 10 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, or 5 to 10 membered heteroaryl, and more preferably is phenyl or napthyl, or a 5 to 10 membered heteroaryl selected from thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, or quinazolinyl, each of which may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms.

In certain other preferred embodiments of the invention, R⁷ is aryl of 5 to 10 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, branched alkyl of 3 to 6 carbon atoms, branched alkenyl of 3 to 6 carbon atoms, or 5 to 10 membered heteroaryl, and more preferably is phenyl or napthyl, or a 5 to 10 membered heteroaryl selected from thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, or quinazolinyl, each of which may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms. In preferred compounds of this embodiment, R, R′, R¹, and R² are each, independently, hydrogen or alkyl of 1 to 6 carbon atoms.

In other preferred embodiments, R⁷ is aryl of 5 to 10 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, or 5 to 10 membered heteroaryl, or more preferably phenyl, wherein said aryl (including phenyl), cycloalkyl or heteroaryl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms. In preferred compounds of this embodiment, at least one of R⁴ and R⁵ is halogen, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 3 carbon atoms, or alkoxy of 1 to 6 carbon atoms. Even more preferred compounds are those in which at least one of R⁴ and R⁵ is halogen, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 3 carbon atoms, or alkoxy of 1 to 6 carbon atoms, and R, R′, R¹, and R² are each, independently, hydrogen or alkyl of 1 to 6 carbon atoms. In other preferred embodiments, R⁷ is aryl of 5 to 10 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a lower alkyl, a perfluoroalkyl of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms or a perfluoroalkoxy of 1 to 3 carbon atoms.

In certain embodiments, R⁷ is selected from the group consisting of:

-   4-methoxy-2-methylphenyl, -   2-chloro-4-(trifluoromethyl)phenyl, -   2-chloro-4-methoxyphenyl, -   2-chloro-4-(trifluoromethoxy)phenyl, -   ({7-[4-methoxy-2-(trifluoromethyl)phenyl, -   4-ethoxy-2-methylphenyl, -   4-ethoxy-2-(trifluoromethyl)phenylamine, -   4-chloro-2-(trifluoromethyl)phenyl, -   4-fluoro-2-(trifluoromethyl)phenyl, -   2-ethyl-4-methoxyphenyl, -   2,4-dichlorophenyl, -   2,4-dimethylphenyl, -   4-isopropyl-2-methoxyphenyl, -   4-isopropoxy-2-(trifluoromethyl)phenyl, -   2-chloro-4-isopropoxyphenyl, -   4-chloro-2-methylphenyl, -   2,6-difluorophenyl, -   2-chloro-6-fluorophenyl, -   2-fluoro-6-(trifluoromethyl)phenyl, -   2,6-bis(trifluoromethyl)phenyl, -   2,3-dichlorophenyl, -   3-chloro-2-fluorophenyl, -   2-chloro-3-methylphenyl, -   2,6-dichloro-4-methoxyphenyl, and -   5-fluoro-2-methoxyphenyl.

In the compounds of the present invention, n is 1, 2 or 3, preferably 1 or 2, and more preferably 1.

In still further preferred embodiments of the invention, the compounds of Formula 1 are:

-   (±)-1-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (+)-1-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (−)-1-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (−)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (+)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (±)-N-[(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methyl]-N-methylamine, -   (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (−)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (+)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (±)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (−)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (+)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (−)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (+)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (−)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (+)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-1-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (±)-1-[7-(1-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(3,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (+)-(1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (−)-1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-1-[7-(2-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-(2′,3′-dihydro-2,7′-bi-1-benzofuran-2′-yl)methanamine, -   (±)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (+)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (−)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (−)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (+)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (±)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine, -   (+)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine, -   (−)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine, -   (±)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (±)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (±)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,

(±)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine,

-   (+)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (−)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-1-[5-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[5-chloro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (−)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (+)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (+)-N-[(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]-N-methylamine, -   (−)-N-[(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]-N-methylamine, -   (±)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-(4-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-1-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-(5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (±)-1-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-(5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (±)-(5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine, -   (−)-1-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (+)-1-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-1-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (±)-1-[7-(3,3-dimethylbutyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (−)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (+)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (±)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (+)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (+)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (−)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (±)-1-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (+)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine, -   (±)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (+)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (−)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-1-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine,     or -   (±)-1-[7-(2-phenylethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,     or a pharmaceutically acceptable salt thereof.

In other preferred embodiments of the invention, the compounds of Formula 1 are:

-   (±)-1-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-{[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-[(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine, -   (+)-{[7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-phenylamine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-methylphenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-chlorophenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-methoxyphenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-[4-(trifluoromethyl)phenyl]amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-fluorophenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3,4-dichlorophenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(2,4-dimethylphenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3,4-dimethylphenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-methylphenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-fluorophenyl)amine, -   (±)—N-2-(aminomethyl)-N-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-7-amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-methoxy-3-methylphenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3,5-difluorophenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-trifluoromethoxy)phenyl]amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-chloro-4-methylphenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3,5-dichlorophenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-chlorophenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-chloro-3-methylphenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3,5-dimethylphenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-chloro-4-fluorophenyl)amine, -   (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(2-fluorophenyl)amine, -   (±)-{[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-fluoro-7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-fluoro-7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-fluoro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-fluoro-7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-fluoro-7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-fluoro-7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-fluoro-7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-[(5-fluoro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine, -   (±)-{[5-fluoro-7-(3-furyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-[(5-fluoro-7-pyridin-2-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine, -   (±)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine, -   (−)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine, -   (+)-{[5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-[(5-fluoro-7-pyridin-4-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine, -   (±)-[(5-fluoro-7-pyrimidin-5-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine, -   (±)-{[7-(2,3-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,4-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[5-fluoro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[5-fluoro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,4-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,6-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclopropanamine, -   (±)-1-cyclopropyl-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methanamine, -   (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclobutanamine, -   (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}ethanamine, -   (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}propan-1-amine, -   (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}propan-2-amine, -   (±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}dimethylamine, -   (±)-1-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}piperidine -   (±)-1-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}morpholine -   (±)-1-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}pyrrolidine -   (±)-{[5-chloro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(3-furyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[(5-chloro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine, -   (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclopropanamine, -   (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}(cyclopropylmethyl)amine, -   (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclobutanamine, -   (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}ethanamine, -   (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}propan-2-amine, -   (±)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}dimethylamine, -   (±)-1-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}piperidine -   (±)-4-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}morpholine -   (±)-4-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}thiomorpholine -   (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}propan-1-amine, -   (±)-1-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}piperazine -   (±)-1-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}pyrrolidine -   (±)-{[(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine, -   (±)-{[7-(2-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2-methoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-({5-methyl-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)amine, -   (±)-{[7-(3-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(3-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(4-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(4-fluorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(4-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(4-methoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-ethyl-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-ethyl-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-isopropyl-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-isopropyl-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-cyclopentyl-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-cyclopentyl-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-isocyano-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-isocyano-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-(trifluoromethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,3-dimethylphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,3-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(3,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,6-dimethylphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(4-butylphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-4-[2-(aminomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-7-yl]benzonitrile -   (±)-{[7-(3-furyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-thien-3-yl-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-pyridin-3-yl-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-[(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine, -   (±)-{[7-(2-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(3-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(4-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(3-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(4-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(3-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(4-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,4-difluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dichlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2-methoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[5-methoxy-7-(3-thienyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,3-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,4-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,5-dimethoxylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(3-chloro-4-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-fluoro-5-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-fluoro-5-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-({7-fluoro-5-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)amine, -   (±)-{[7-fluoro-5-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-fluoro-5-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-fluoro-5-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-fluoro-5-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-({7-fluoro-5-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)amine, -   (±)-{[7-fluoro-5-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-fluoro-5-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-fluoro-5-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[7-fluoro-5-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-({7-fluoro-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)amine, -   (±)-{[7-fluoro-5-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}ethanamine, -   (±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclopropanamine, -   (±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclobutanamine, -   (±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}propan-2-amine, -   (±)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[{[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-[(N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-N-methyl-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-N-methyl-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-[(N-methyl-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (+)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-N-methyl-1-(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine, -   (±)-[(N-methyl-1-[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-{[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (−)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (+)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (−)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (+)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (+)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (−)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(5-chloro-2-methoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine, -   (±)-[(5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-[(5-chloro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2-methoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(3-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(3-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(4-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(4-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(4-fluorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(4-methoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (+)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (−)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,3-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,5-dimethoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(3-chloro-4-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(3-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(4-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(3-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(4-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(3-methylphenyl)-5-phenyl-2,3-dihydro     1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(4-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(3-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(4-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-(2,4-difluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[N-methyl-1-[7-phenyl-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-N-methyl-1-[7-(3-methylphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-N-methyl-1-[7-(3-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-N-methyl-1-[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-N-methyl-1-[7-(3,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-N-methyl-1-[7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-N-methyl-1-[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-{[7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-N-methyl-1-[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (±)-{[7-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-fluoro-5-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{[7-fluoro-5-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{7-fluoro-5-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine, -   (±)-{7-fluoro-5-[2-methoxyphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine, -   (±)-{7-fluoro-5-[3-methylphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine, -   (±)-{7-fluoro-5-[3-chlorophenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine, -   (±)-{[7-fluoro-5-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{7-fluoro-5-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine, -   (±)-{7-fluoro-5-[3-methoxyphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine, -   (±)-{7-fluoro-5-[4-methylphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine, -   (±)-{7-fluoro-5-[4-chlorophenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine, -   (±)-{[7-fluoro-5-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (±)-{7-fluoro-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine, -   (±)-{7-fluoro-5-[4-methoxyphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine, -   (+)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (−)     {[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (R)-[7-(2-chloro-phenyl)-(5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl)methyl-amine, -   (R)-[7-(2,6-dichloro-phenyl)-5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl]ethylamine, -   (R)-[7-(2,6-dichloro-phenyl)-5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl]dimethylamine, -   {[(2R)-7-(5-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   {[(2R)-7-(4-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (−)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (+)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine, -   (±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine, -   (±)-{2-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine, -   (±)-{2-[7-(2-methoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine, -   (±)-{N-methyl-1-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-{N-methyl-1-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (−)-{N-methyl-1-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, -   (+)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (−)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (−)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (+)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (+)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (−)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (−)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (+)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (−)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine, -   (−)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,     or -   (+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine;     or a pharmaceutically acceptable salt thereof.

The compounds of Formula 1 have affinity for and agonist or partial agonist activity at the 2c subtype of brain serotonin receptors and are thus of interest for the treatment of mental disorders, including psychotic disorders such as schizophrenia including paranoid type, disorganized type, catatonic type, and undifferentiated type, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, and psychotic disorder not otherwise specified; L-DOPA-induced psychosis; psychosis associated with Alzheimer's dementia; psychosis associated with Parkinson's disease; psychosis associated with Lewy body disease; bipolar disorders such as bipolar I disorder, bipolar II disorder, and cyclothymic disorder; depressive disorders such as major depressive disorder, dysthymic disorder, substance-induced mood disorder, and depressive disorder not otherwise specified; mood episodes such as major depressive episode, manic episode, mixed episode, and hypomanic episode; anxiety disorders such as panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, substance-induced anxiety disorder, and anxiety disorder not otherwise specified; adjustment disorders such as adjustment disorders with anxiety and/or depressed mood; intellectual deficit disorders such as dementia, Alzheimer's disease, and memory deficit; eating disorders (e.g., hyperphagia, bulimia or anorexia nervosa) and combinations of these mental disorders that may be present in a mammal. For example, mood disorders such as depressive disorders or bipolar disorders often accompany psychotic disorders such as schizophrenia. A more complete description of the aforementioned mental disorders can be found in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Washington, D.C., American Psychiatric Association (1994), incorporated herein by reference in its entirety.

The compounds of formula 1 are also of interest for the treatment of epilepsy; migraines; sexual dysfunction; sleep disorders; substance abuse, including addiction to alcohol and various drugs, including cocaine and nicotine; gastrointestinal disorders, such as malfunction of gastrointestinal motility; and obesity, with its consequent comorbidities including Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers, some infertility, and early mortality.

The compounds of Formula 1 can also be used to treat central nervous system deficiencies associated, for example, with trauma, stroke, and spinal cord injuries. The compounds of Formula 1 can therefore be used to improve or inhibit further degradation of central nervous system activity during or following the malady or trauma in question. Included in these improvements are maintenance or improvement in motor and motility skills, control, coordination and strength.

In certain embodiments, the present invention therefore provides methods of treating, each of the conditions listed above in a patient, preferably in a human, the methods including administering a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt thereof to a patient suffering from such a condition.

In other embodiments, the invention relates to compositions comprising at least one compound of Formula 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions include pharmaceutical compositions for treating or controlling disease states or conditions of the central nervous system. In certain embodiments, the compositions comprise mixtures of one or more compounds of Formula 1.

Certain of the compounds of Formula 1 contain stereogenic carbon atoms or other chiral elements (i.e. chirality axis) and thus give rise to stereoisomers, including enantiomers, diastereomers, and in the case of biphenyls, the formation of atropisomers. For definitions and an extensive discourse on atropisomers, see: Eliel, E. L. Stereochemistry of Organic Compounds (John Wiley & Sons, 1994, p 1142), which is incorporated herein by reference in its entirety. Although the stereochemistry is not shown in Formula 1, Formula 1 includes all of the stereoisomers of the 1-(2,3-dihydro-1-benzofuran-2-yl)alkanamine derivatives, as well as mixtures of the stereoisomers. Throughout this application, the name of the product, where the absolute configuration of an asymmetric center is not indicated, is intended to embrace the individual stereoisomers as well as mixtures of stereoisomers. When it is necessary to distinguish the enantiomers from one another and from the racemate, the sign of the optical rotation [(+), (−) and (±)] is utilized. Furthermore, throughout this application, the designations R* and S* are used to indicate relative stereochemistry, employing the Chemical Abstracts convention which automatically assigns R* to the lowest numbered asymmetric center.

Where a stereoisomer is preferred, it may, in some embodiments, be provided substantially free of the corresponding stereoisomer. Thus, a stereoisomer substantially free of the corresponding stereoisomer refers to a compound that is isolated or separated via separation techniques or prepared free of the corresponding stereoisomer. “Substantially free,” as used herein, means that the compound is made up of a significantly greater proportion of one stereoisomer. In preferred embodiments, the compound is made up of at least about 90% by weight of a preferred stereoisomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred stereoisomer. Preferred stereoisomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred stereoisomers can be prepared by methods described herein. Methods for the preparation of preferred stereoisomers are described, for example, in Jacques, et al., Enantiomers. Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972), each of which is hereby incorporated by reference in its entirety.

This invention also provides processes for preparing compounds of formula I which processes include one of the following:

a) reacting a compound of formula 7

wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined herein, with sodium azide and reducing the product to give a compound of formula 1 wherein n is 1 and R and R′ are both H; or b) reacting a compound of formula 7 as defined above with an amine of formula NHRR′ where R and R′ are as defined herein to give a corresponding compound of formula 1 wherein n is 1; or c) reacting a compound of formula 7 as defined above with sodium cyanide followed by reduction to give a compound of formula 1 wherein n is 2 and R and R′ are both H; d) converting a compound of formula 1 as defined herein to a pharmaceutically acceptable salt or vice versa; or e) isolating a specific enantiomer or diastereomer of a compound of formula 1 or a pharmaceutically acceptable salt thereof as defined herein from a mixture thereof.

The 1-(2,3-dihydro-1-benzofuran-2-yl)alkanamine derivatives of Formula 1 may be prepared as illustrated in Scheme I.

Variables used are as defined for Formula 1, unless otherwise noted. The appropriately substituted phenol (2) is alkylated with an appropriately substituted allyl bromide or alcohol (3) in the presence of a suitable base such as potassium carbonate in a solvent such as N,N-dimethylformamide. The phenols, allyl bromides, and allyl alcohols appropriate for the synthesis of the compounds of formula I are either commercially available or can readily be prepared by one skilled in the art. The resulting allyl ether (4) is treated in refluxing mesitylene or other suitable high boiling solvent to afford the desired Claisen rearrangement product. The 2-allyl phenol (5) intermediate is subjected to epoxidation of the double bond with 3-chloroperoxybenzoic acid in dichloromethane. The resulting epoxy phenol intermediate is treated with a suitable base such as potassium carbonate in a solvent such as methanol to induce cyclization to give the 2,3-dihydro-1-benzofuran-2-yl)methanol (6). Treatment of (6) with p-toluenesulfonyl chloride and a suitable base such as pyridine affords the tosylate (7). Conversion of (7) to the amine (1) can be accomplished, for example, by treatment with sodium azide in a solvent such as dimethylsulfoxide followed by reduction of the azide or direct treatment with an appropriately substituted amine to provide the compounds of Formula 1. Additionally, longer alkyl chains (i.e. 2-aminoethyl) may be prepared, for example, via treatment of (7) with sodium cyanide in a solvent such as dimethylsulfoxide followed by reduction of the nitrile.

The preparation of appropriately substituted phenols (2) in Scheme I, in particular the 7-aryl substituted phenols, is illustrated in Scheme Ia.

Utilization of a 2-halogenated methoxy benzene or a suitably protected 2-halogenated phenol (2a) permits the introduction of the aromatic substitutent through a palladium-catalyzed cross coupling reaction (i.e. Suzuki reaction) with the desired boronic acid. Treatment of (2a) with a catalyst such as dichlorobis(tri-o-tolylphosphine)-palladium(II) in the presence of a suitable base such as potassium carbonate in a solvent such as dioxane provides the biaryl system. Subsequent removal of the protecting group, in this example demethylation of (2b) via reaction with borontribromide in dichloromethane affords the phenol (2).

Alternatively, the phenols (2) may be prepared by a reversal of the inherent reactivity associated with the partners in the cross-coupling reaction as shown in Scheme Ib.

Installation of the biaryl system may also be accomplished via a palladium-catalyzed cross coupling reaction (i.e. Suzuki reaction) of appropriate derivatives of 2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (7) with the desired boronic acid (Scheme Ic). Treatment of (7) with a catalyst such as dichlorobis(tri-o-tolylphosphine)-palladium(II) in the presence of a suitable base such as potassium carbonate in a solvent such as dioxane provides the biaryl system.

Alternatively, installation of the biaryl system may be accomplished via a palladium-catalyzed cross coupling reaction (i.e. Suzuki reaction) of appropriate 1-(2,3-dihydro-1-benzofuran-2-yl) derivatives (1a) in either racemic or stereochemically pure form following separation of the enantiomers. For example, treatment of 1a and a boronic acid (Scheme Id) with a catalyst such as dichlorobis(tri-o-tolylphosphine)-palladium(II) in the presence of a suitable base such as potassium carbonate (as described previously) provides the desired biaryl system. Deprotection of the resultant product from the coupling procedure with, for example, iodotrimethylsilane in a solvent such as acetonitrile (for X=NRCbz) then affords the title compounds of Formula 1.

The compounds of Formula 1 can also be prepared in a stereoselective manner as illustrated in Scheme II.

Protection of the 2-allyl phenol (5) with a suitable protecting group such as benzyl by treatment with benzyl bromide in the presence of a suitable base such as potassium carbonate in a solvent such as N,N-dimethylformamide gives the benzyl ether (8). Treatment of (8) utilizing extant methodology known to one skilled in the art for the stereoselective oxidation of double bonds such as the Sharpless Asymmetric Dihydroxylation (A-D) provides the diol (9) in stereochemically enriched form. Many methods are available to one skilled in the art for the transfer of the stereochemical information present in (9) into the compounds of formula (1) with retention of stereochemical integrity. One such method involves deprotection of the benzyl ether with catalytic palladium on carbon under a hydrogen atmosphere (45 psi) in a solvent, such as methanol, to provide triol (10). Formation to the previously described 2,3-dihydro-1-benzofuran-2-yl)methanol (6) can be accomplished by treatment of (9) with hydrogen bromide in acetic acid to provide the intermediate vicinal acetoxy bromide followed by cyclization with a suitable base such as potassium carbonate in a solvent such as methanol.

Alternatively, the compounds of Formula 1 can be prepared via selective mono-protection of diol (9) with a suitable protecting group as illustrated in Scheme III.

Treatment of (9) with tert-butyldimethylsilyl chloride in the presence of a suitable base such as imidazole in a solvent such as N,N-dimethylformamide followed by deprotection of the benzyl ether (as previously described) with catalytic palladium on carbon under a hydrogen atmosphere gives phenol (12). Cyclodehydration of (12) using standard Mitsunobu conditions, such as triphenylphosphine in the presence of diethylazodicarboxylate in a solvent such as toluene, provides the 2,3-dihydro-1-benzofuran-2-yl)methanol (13) protected as the silyl ether. Removal of the silyl ether in (13) using standard conditions such as tetrabutylamonnium fluoride in a solvent such as tetrahydrofuran then provides the alcohol (6) which can be converted to the compounds of the current invention as previously described (Scheme I).

In lieu of a protecting group, diol (9) can be converted to the mono-tosylated derivative (12a) by treatment with p-toluenesulfonyl chloride and a suitable base such as pyridine to give the desired product, as illustrated in Scheme IV.

Deprotection of the benzyl ether with catalytic palladium on carbon gives phenol (12b) followed by cyclodehydration with triphenylphosphine in the presence of diethylazodicarboxylate (as previously described) provides the aforementioned 2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (7).

An additional route to the production of stereochemically enriched compounds of Formula 1 is illustrated in Scheme V.

Palladium or transition metal catalyzed transposition of the double bond present in the previously described 2-allyl benzyl ether (8) using an appropriate catalyst such as dichlorobis(acetonitrile)palladium(II) in dichloromethane provides styrene derivative (14). Treatment of (14) with selenium dioxide in dioxane provides the carbonyl derivative (15). Reduction of the carbonyl to the allylic alcohol (16) can be accomplished by treatment with an appropriate reducing agent such as tetrabutylammonium borohydride in a solvent such as dichloromethane. The allylic alcohol (16) provides a suitable intermediate for the stereoselective introduction of oxygenation that permits transfer of this stereochemical integrity into the compounds of formula (1). The Sharpless Asymmetric Epoxidation (A-E) reaction is a general method for the stereoselective epoxidation of allylic alcohols and treatment of (16) under the appropriate conditions provides epoxy alcohol (17) with a high degree of stereoselectivity. The alcohol present in (17) can then be tosylated with p-toluenesulfonyl chloride as previously described to give derivative (18). Deprotection of the benzyl ether with concomitant regioselective opening of the epoxide maintaining the stereochemical information introduced by the Sharpless A-E is accomplished under the appropriate conditions by treatment of (18) with palladium on carbon under a hydrogen atmosphere in a solvent such as ethanol. Cyclodehydration using Mitsunobu conditions as previously described then affords 2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (7).

The preparation of compounds of Formula 1 can also be accomplished in a stereospecific manner utilizing an optically pure commercially available intermediate. This method is described in detail in a copending U.S. provisional patent application entitled “Process For Stereospecific Synthesis of Dihydrobenzofuran Derivatives,” filed in the name of Dahui Zhou, et al. on the same date as the instant application. That application is incorporated herein by reference in its entirety for all purposes. As shown in Scheme VI, below, for example, reaction of benzyl(S)-(±)-glycidyl ether with the anion obtained by treatment of 2-bromoanisole with an alkyllithium such as n-butyllithium provides the resultant epoxy intermediate. Ring opening of the epoxide with a Lewis acid such as borontrifluoride diethyletherate provides diol (9a) with the primary alcohol protected as the benzyl ether. Deprotection of the methoxy group in 9a by treatment with 30% hydrogen bromide in acetic acid results in concomitant formation of intermediate vicinal acetoxy bromide (10a) followed by removal of the acetate with aqueous hydrogen chloride to provide diol (13a). Cyclodehydration with triphenylphosphine in the presence of diethylazodicarboxylate (as previously described) provides the desired 2-(bromomethyl)-2,3-dihydro-1-benzofuran (7b) that can be converted to the 7-bromo derivative (7c) by treatment with bromine in acetic acid.

A further method for the synthesis of stereochemically enriched compounds of Formula 1 is described in detail in copending U.S. provisional patent application entitled “Asymmetric Synthesis of 2-(methylamino)dihydrobenzofurans,” filed in the name of Alexander Gontcharov, et al. on the same date as the instant application. That application is incorporated herein by reference in its entirety for all purposes. That method is illustrated in the preparation of the compound 2R-(−)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-2-aminomethylbenzofuran hydrochloride shown in Scheme VII.

In certain embodiments, the invention relates to compositions comprising at least one compound of Formula 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions are prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), which is incorporated herein by reference in its entirety. Pharmaceutically acceptable carriers are those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable.

The compounds of Formula 1 can be administered orally or parenterally, neat, or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials. In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

The compounds of Formula 1 can be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of Formula 1 can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of Formula 1 can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient can also be suitable. A variety of occlusive devices can be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The amount of compound of formula 1 provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compounds of formula 1 are provided to a patient suffering from a condition in an amount sufficient to treat or at least partially treat the symptoms of the condition and its complications. An amount adequate to accomplish this is a “therapeutically effective amount” as described previously herein. The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age, and response pattern of the patient. The treatment of substance abuse follows the same method of subjective drug administration under the guidance of the attending physician. Generally, a starting dose is about 5 mg per day with gradual increase in the daily dose to about 150 mg per day, to provide the desired dosage level in the patient.

In certain embodiments, the present invention is directed to prodrugs of compounds of Formula 1. The term “prodrug,” as used herein, means a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula 1. Various forms of prodrugs are known in the art such as those discussed in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Delivery Reviews, 8:1-38 (1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is hereby incorporated by reference in its entirety.

Intermediate 1 1-allyl-2-(benzyloxy)-4-methoxybenzene

To a solution of 2-allyl-5-methoxyphenol (20.30 g, 0.124 mol) in DMF (500 mL) was added potassium carbonate (68.35 g, 0.495 mol) followed by benzyl bromide (23.26 g, 0.136 mol) and tetrabutylammonium iodide (4.57 g, 0.012 mol). The reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (1000 mL) to dissolve any solids and extracted with diethyl ether (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:19) provided 28.44 g (90%) of 1-allyl-2-(benzyloxy)-4-methoxybenzene as a colorless oil. R_(f)=0.88 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C₁₇H₁₈O₂: C, 80.28; H, 7.13. Found: C, 82.43; H, 7.09.

Intermediate 2 (±)-3-[2-(benzyloxy)-4-methoxyphenyl]propane-1,2-diol

To a suspension of AD-mix-α (156.55 g) in water:tert-butyl alcohol (1:1, 800 mL) cooled to 0° C. was slowly added via an addition funnel a solution of 1-allyl-2-(benzyloxy)-4-methoxybenzene (28.44 g, 0.112 mol) in water:tert-butyl alcohol (1:1, 200 mL) and the reaction mixture was allowed to stir at 0° C. for 12 h. The reaction mixture was quenched by the addition of sodium sulfite. The reaction mixture was diluted with water (500 mL) and ethyl acetate (500 mL). The aqueous phase was separated and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:2) gave 30.50 g (95%, 27% ee) of (±)-3-[2-(benzyloxy)-4-methoxyphenyl]propane-1,2-diol as a white crystalline solid. mp 82-86° C.; Anal. calcd. for C₁₇H₂₀O₄: C, 70.81; H, 6.99. Found: C, 70.78; H, 7.16.

Intermediate 3 (±)-3-[2-(benzyloxy)-4-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate

To a solution of (±)-3-[2-(benzyloxy)-4-methoxyphenyl]propane-1,2-diol (30.50 g, 0.106 mol) in anhydrous pyridine (600 mL) cooled to 0° C. under a nitrogen atmosphere was added p-toluenesulfonyl chloride (22.18 g, 0.116 mol). The reaction mixture was allowed to stir at 0° C. for 12 h. The reaction mixture was quenched by the addition of water (10 mL). The reaction mixture was diluted with ethyl acetate (750 mL) and the organic layer was washed with aqueous hydrogen chloride (6 N, 4×400 mL), saturated aqueous sodium chloride (300 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) gave 42.84 g (91%) of (+)-3-[2-(benzyloxy)-4-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. R_(f)=0.28 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C₂₄H₂₆O₆S: C, 65.14; H, 5.92. Found: C, 64.59; H, 5.72.

Intermediate 4 (±)-2-hydroxy-3-(2-hydroxy-4-methoxyphenyl)propyl 4-methylbenzenesulfonate

To a solution of (±)-3-[2-(benzyloxy)-4-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate (42.84 g, 0.097 mol) in ethanol (600 mL) was added palladium on carbon (10 wt. %, 5.81 g) and the reaction mixture was shaken under an H₂ atmosphere (50 psi) for 6 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide 32.27 g (95%) of (±)-2-hydroxy-3-(2-hydroxy-4-methoxyphenyl)propyl 4-methylbenzenesulfonate as a colorless oil. R_(f)=0.34 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C₁₇H₁₈O₅S: C, 61.06; H, 5.43. Found: C, 60.70; H, 5.37.

Intermediate 5 (±)-(6-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (±)-2-hydroxy-3-(2-hydroxy-4-methoxyphenyl)propyl 4-methylbenzenesulfonate (32.27 g, 0.092 mol) in toluene (1000 mL) cooled to 0° C. was added triphenylphosphine (27.62 g, 0.105 mol) followed by dropwise addition of diethylazodicarboxylate (18.34 g, 0.105 mol) and the reaction mixture was allowed to stir at 0° C. for 15 min. The reaction mixture was quenched by the addition of water (10 mL). The solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:19) provided 22.53 g (74%) of (±)-(6-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. R_(f)=0.67 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C₁₇H₁₈O₅S: C, 61.06; H, 5.43. Found: C, 60.70; H, 5.37.

Intermediate 6 (±)-(6-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (±)-(5-methoxy-2,3-dihydro-1H-inden-2-yl)methyl 4-methylbenzenesulfonate (13.5 g, 40.5 mmol) in dichloromethane (250 mL) at −70° C. was added boron tribromide (27.0 mL, 1.0 N in dichloromethane) over 15 min. The reaction mixture was allowed to stir at −70° C. for an additional 15 minutes and allowed to warm to room temperature over 6 h. The reaction mixture was quenched with ice water and the product extracted with ethyl acetate (600 mL). The organic layer dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4→1:1) afforded 10.15 g (79%) of (±)-(6-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow solid. mp 107-110° C.; Anal. calcd. for C₁₆H₁₆O₅S: C, 59.99; H, 5.03. Found: C, 59.21; H, 5.05.

Intermediate 7 (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (±)-(6-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (8.67 g, 27.2 mmol) in anhydrous dichloromethane (300 mL) at 0° C. was added diisopropylethylamine (4.22 g, 32.6 mmol) followed by trifluoromethanesulfonic anhydride (8.45 g, 29.9 mmol) and the reaction mixture was allowed to stir at 0° C. for 1 h. The reaction mixture was quenched with water (300 mL) and diluted with dichloromethane (400 mL), The combined organic layers were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4→2:3) afforded 10.3 g (84%) of (±)-(6-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a tan solid. To a solution of (±)-(6-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 4.43 mmol) in dioxane (50 mL) was added phenylboronic acid (1.08 g, 8.86 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.884 mmol), and lithium chloride (0.787 g, 17.43 mmol) and the reaction mixture was heated at 90° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with water (500 mL) and ethyl acetate (500 mL). The organic layer was separated and washed with water (200 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 0.170 g (10%) of (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as an oil. ¹H NMR (DMSO d₆) δ_(H) 7.75 (d, 2H); 7.56 (d, 2H); 7.42 (m, 4H); 7.28 (t, 1H); 7.21 (d, 1H); 7.08 (d, 1H); 6.92 (s, 1H); 4.98 (m, 1H); 4.24 (dd, 1H); 4.18 (q, 1H); 3.29 (dd, 1H); 2.88 (dd, 1H); 2.46 (s, 3H).

Intermediate 8 2-allyl-6-chloro-3-(trifluoromethyl)phenol

To a solution of 2-chloro-5-trifluoromethyl-phenol (10.00 g, 0.05 mol) in N,N-dimethylformamide (500 mL) was added potassium carbonate (28.12 g, 0.209 mol) followed by allyl bromide (7.38 g, 0.061 mol) and the reaction was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (500 mL) to dissolve any solids and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give 2-(allyloxy)-1-chloro-4-(trifluoromethyl)benzene as a colorless oil. The oil was re-dissolved in mesitylene (35 mL) and heated at reflux for 12 h. Removal of the solvent in vacuo provided a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) provided 9.6 g (96%) of 2-allyl-6-chloro-3-(trifluoromethyl)phenol as a amber oil. R_(f)=0.66 (silica, ethyl acetate:hexanes 1:4); ¹H NMR (DMSO-d₆) δ_(H) 9.84 (s, 1H); 7.43 (d, 2H); 7.16 (d, 1H); 5.84 (m, 1H); 4.95 (d, 1H); 4.89 (d, 1H); 3.46 (d, 2H).

Intermediate 9 (±)-[7-chloro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanol

To a solution of 6-chloro-3-(trifluoromethyl)-2-vinylphenol (9.67 g, 0.043 mol) in dichloromethane 225 mL) was added 3-chloroperoxybenzoic acid (77%, 21.15 g, 0.122 mol). The reaction mixture was allowed to stir at room temperature for 8 h. The reaction mixture was washed with a 1:1 solution of 10% sodium sulfite:saturated sodium bicarbonate (2×200 mL). The solvent was removed in vacuo to give crude yellow oil. The oil was diluted with methanol (100 mL) and added to a solution of potassium carbonate (16.5 g, 0.119 mol) and methanol (825 mL) and the solution was allowed to stir at room temperature 2 h. The solvent was removed in vacuo. The residue was washed with water (1000 mL) and ethyl acetate (500 mL). The aqueous layer was acidified with 1 N aqueous hydrogen chloride and washed with ethyl acetate (500 mL). The combined organics were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate) and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4) provided 6.71 g (70%) of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol as a yellow oil. R_(f)=0.20 (silica, ethyl acetate:hexanes 1:4). Anal. calcd. for C₁₀H₈ClF₃O₂: C, 47.55; H, 3.19. Found C, 49.39; H, 3.57.

Intermediate 10 (±)-[7-chloro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

To a solution of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol (8.5 g, 0.034 mol) in pyridine (150 mL) cooled to 0° C. was added p-toluenesulfonyl chloride (7.06 g, 0.037 mol) and the reaction mixture was allowed to stir at 0° C. for 12 h. The reaction mixture was quenched by the addition of water (75 mL), diluted with diethyl ether (600 mL), washed with aqueous hydrogen chloride (1.0 M, 750 mL), water (200 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) afforded 7.0 g (51%) of (±)-[7-chloro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid R_(f)=0.60 (silica, ethyl acetate:hexanes 3:7); mp 89-92° C.; Anal. calcd. for C₁₇H₁₄ClF₃O₄S C, 50.19; H, 3.47. Found C, 50.30; H, 3.35.

Intermediate 11 (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol

Treatment of 2-allyl-6-cyclopentylphenol (6.97 g, 0.0344 mol) with 3-chloroperoxybenzoic acid (17.83 g, 0.1033 mol, 77%) and potassium carbonate (14.0 g, 0.1013 mol) generally according to the procedure described for Intermediate 9 afforded 4.1 g (54%) of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol as a yellow oil. R_(f)=0.58 (silica, ethyl acetate:hexanes 3:7); Anal. calcd. for C₁₄H₁₈O₂: C, 77.03; H, 8.31. Found C, 76.5; H, 8.44.

Intermediate 12 (±)-benzyl (7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

To a suspension of (7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.4 g, 9.46 mmol) in tetrahydrofuran (100 mL) cooled to 0° C. was added diisopropylethylamine (2.14 g, 16.58 mmol) followed by benzyl chloroformate (20.08 g, 12.19 mmol) and the reaction mixture was allowed to stir for 15 min. The reaction mixture was quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 2.52 g (76%) of (±)-benzyl (7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a yellow oil. R_(f)=0.21 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C₂₂H₂₅NO₃: C, 75.19; H, 7.17; N, 3.99. Found C, 74.74; H, 7.02; N, 3.85. Chiral HPLC separation of (±)-benzyl (7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol:hexane 1:1) provided two fractions. Fraction 1 (R_(t) 9.678 min, Chiralcel OJ, ethanol:hexane 1:1); Fraction 2 (R_(t)=12.824 min, Chiralcel OJ, ethanol:hexane 1:1).

Intermediate 13 (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methanol

To a solution of 4-chloro-2-cyclohexylphenol (23.00 g, 0.109 mol) in N,N-dimethylformamide (600 mL) was added sodium hydride (4.56 g, 0.114 mol, 60 wt. %) followed by allyl bromide (14.51 g, 0.120 mol) and the reaction mixture was allowed to stir at room temperature for 5 h. The solvent was removed in vacuo and the residue diluted with water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate), and the solvent removed in vacuo to give 29.0 g of 1-(allyloxy)-4-chloro-2-cyclohexylbenzene as a brown oil. Treatment of the allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 provided 18.0 g of 2-allyl-4-chloro-6-cyclohexylphenol. Treatment of the phenol (6.5 g, 0.026 mol) with 3-chloroperoxybenzoic acid (9.88 g, 0.045 mol, 77%) followed by potassium carbonate (10.00 g, 0.072 mol) generally according to the procedure described for Intermediate 9 afforded 4.6 g (67%) of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. mp 67-69° C.; Anal. calcd. for C₁₅H₁₉ClO₂: C, 67.54; H, 7.18. Found: C, 67.81; H, 6.98.

Intermediate 14 (±)-methyl (5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Treatment of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.20 g, 7.28 mmol) with diisopropylethylamine (2.94 g, 22.7 mmol) and methyl chloroformate (1.08 g, 11.4 mmol) generally according to the procedure described for Intermediate 12 provided 2.30 g (93%) of (±)-methyl (5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a white solid. mp 100-103° C.; Anal. calcd. for C₁₇H₂₂ClNO₃: C, 63.06; H, 6.85; N, 4.33. Found: C, 63.16; H, 6.3; N, 4.25.

Intermediate 15 (±)-3-[3-benzyl-2-(benzyloxy)phenyl]propane-1,2-diol

Treatment of 2-allyl-6-benzylphenol (12.11 g, 0.054 mol) with potassium carbonate (30.00 g, 0.217 mol), benzyl bromide (10.67 g, 0.062 mol), and tetrabutylammonium iodide (2.01 g, 0.005 mol) generally according to the procedure described for Intermediate 1 provided 1-allyl-3-benzyl-2-(benzyloxy)benzene. Treatment of 1-allyl-3-benzyl-2-(benzyloxy)benzene (16.35 g, 0.052 mol) with AD-mix-ax (76.02 g) generally according to the procedure described for Intermediate 2 gave 9.82 (54%, 25% ee) of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]propane-1,2-diol as a white crystalline solid. mp 55-58° C.; Anal. calcd. for C₂₃H₂₄O₃: C, 79.28; H, 6.94. Found: C, 78.89; H, 6.96.

Intermediate 16 (±)-3-[3-benzyl-2-(benzyloxy)phenyl]-2-hydroxypropyl 4-methylbenzenesulfonate

Treatment of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]propane-1,2-diol (9.76 g, 0.028 mol) with p-toluenesulfonyl chloride (5.87 g, 0.031 mol) in pyridine (250 mL) generally according to the procedure described for Intermediate 3 gave 9.88 g (70%) of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C₃₀H₃₀O₅S: C, 71.69; H, 6.02. Found: C, 70.41; H, 6.14.

Intermediate 17 (±)-3-(3-benzyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate

Treatment of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]-2-hydroxypropyl 4-methylbenzenesulfonate (9.72 g, 0.019 mol) with palladium on carbon (0.97 g, 10 wt. %) generally according to the procedure described for Intermediate 4 provided 7.34 g (92%) of (±)-3-(3-benzyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C₂₃H₂₄O₅S: C, 66.97; H, 5.86. Found: C, 66.11; H, 5.95.

Intermediate 18 (±)-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-3-(3-benzyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate (7.29 g, 0.018 mol) with triphenylphosphine (5.10 g, 0.019 mol) and diethylazodicarboxylate (3.39 g, 0.019 mol) generally according to the procedure described for Intermediate 5 afforded 6.57 g (94%) of (i)-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C₂₃H₂₂O₄S: C, 70.03; H, 5.62. Found: C, 68.97; H, 5.42.

Intermediate 19 (±)-benzyl (7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Treatment of (±)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (2.0 g, 8.36 mmol) with diisopropylethylamine (1.62 g, 12.56 mmol) and benzyl chloroformate (1.64 g, 9.61 mmol) generally according to the procedure described for Intermediate 12 provided 2.96 g (95%) of (±)-benzyl (7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C₂₄H₂₃NO₃: C, 77.19; H, 6.21; N, 3.75. Found C, 75.58; H, 6.42; N, 3.55. Chiral HPLC separation of (±)-benzyl (7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OD, methanol) provided two fractions. Fraction 1 (R_(t)=12.085 min, Chiralcel OD, methanol); Fraction 2 (R_(t)=17.945 min, Chiralcel OD, methanol).

Intermediate 20 (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of 2-allyl-6-isopropylphenol (8.81 g, 0.05 mmol) with 3-chloroperoxybenzoic acid (22.43 g, 0.13 mol, 77%)) followed by potassium carbonate (13.82 g, 0.1 mol) generally according to the procedure described for Intermediate 9 provided (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol (3.45 g, 0.018 mol) with p-toluenesulfonyl chloride (3.92 g, 0.021 mol) generally according to the procedure described for Intermediate 10 afforded 4.91 g (79%) (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C₁₉H₂₂O₄S C, 65.87; H, 6.4. Found C, 65.63; H, 6.32.

Intermediate 21 (±)-benzyl (7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Treatment of (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.2 g, 9.66 mmol) with diisopropylethylamine (3.12 g, 24.15 mmol) and benzyl chloroformate (1.81 g, 10.63 mmol) generally according to the procedure described for Intermediate 12 gave 1.2 g (59%) of (±)-benzyl (7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C₂₀H₂₃NO₃: C, 73.82; H, 7.12; N, 4.3. Found C, 73.32; H, 7.33; N, 4.15. Chiral HPLC separation of (±)-benzyl (7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol) provided two fractions. Fraction 1 (R_(t)=9.319 min, Chiralcel OJ, ethanol); Fraction 2 (R_(t)=11.868 min, Chiralcel OJ, ethanol).

Intermediate 22 2-allyl-4-chloro-6-isopropyl-3-methylphenol

Treatment of 4-chloro-2-isopropyl-5-methylphenol (10.00 g, 0.054 mol) with potassium carbonate (29.94 g, 0.217 mol) and allyl bromide (7.86 g, 0.065 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 8.92 g (73%) of 2-allyl-4-chloro-6-isopropyl-3-methylphenol as a colorless oil. R_(f)=0.85 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C₁₃H₁₇ClOC: C, 69.48; H, 7.62. Found: C, 69.87; H, 7.43.

Intermediate 23 (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of 2-allyl-4-chloro-6-isopropyl-3-methylphenol (8.88 g, 0.04 mmol) with 3-chloroperoxybenzoic acid (13.63 g, 0.079 mol, 77%)) followed by potassium carbonate (10.92 g, 0.079 mol) generally according to the procedure described for Intermediate 9 provided (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (5.95 g, 0.025 mol) with p-toluenesulfonyl chloride (5.66 g, 0.03 mol) generally according to the procedure described for Intermediate 10 afforded 6.71 g (69%) (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 103-105° C.; Anal. calcd. for C₂₀H₂₃ClO₄S C, 60.83; H, 5.87. Found C, 60.67; H, 5.88.

Intermediate 24 (±)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Treatment of (±)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (3.41 g, 12.3 mmol) with diisopropylethylamine (1.99 g, 14.2 mmol) and benzyl chloroformate (2.42 g, 14.2 mmol) generally according to the procedure described for Intermediate 12 gave 3.74 g (81%) of (±)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C₂₁H₂₄ClNO₃: C, 67.46; H, 6.47; N, 3.75. Found C, 67.01; H, 6.52; N, 3.56. Chiral HPLC separation of (±)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, ethanol) provided two fractions.

Intermediate 25 (−)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Fraction 1 obtained as a white solid from the separation of (±)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (R_(t)=4.132 min, Chiralpak AD, ethanol). [α]_(D) ²⁵=−38.52 (c 10.0 in methanol); mp 59-62° C.; Anal. calcd. for C₂₁H₂₄ClNO₃: C, 67.46; H, 6.47; N, 3.75. Found C, 67.26; H, 6.41; N, 3.36.

Intermediate 26 (±)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Fraction 2 obtained as a white solid from the separation of (±)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (R_(t)=5.393 min, Chiralpak AD, ethanol). [α]_(D) ²⁵=+37.84 (c 10.0 in methanol); mp 59-62° C.; Anal. calcd. for C₂₁H₂₄ClNO₃: C, 67.46; H, 6.47; N, 3.75. Found C, 67.2; H, 6.49; N, 3.58.

Intermediate 27 1-allyl-2-(benzyloxy)-3-tert-butylbenzene

Treatment of 2-allyl-6-tert-butylphenol (12.5 g, 0.066 mol) with potassium carbonate (27.24 g, 0.197 mol), benzyl bromide (11.80 g, 0.069 mol), and tetrabutylammonium iodide (2.43 g, 6.57 mmol) generally according to the procedure described for Intermediate 1 provided 16.2 g (88%) of 1-allyl-2-(benzyloxy)-3-tert-butylbenzene as a colorless oil. Anal. calcd. for C₂₀H₂₄O: C, 85.67; H, 8.63. Found: C, 86.27; H, 8.77.

Intermediate 28 (±)-3-[2-(benzyloxy)-3-tert-butylphenyl]propane-1,2-diol

To a suspension of potassium ferricyanide (57.00 g, 0.173 mol), potassium carbonate (24.00 g, 0.174 mol), hydroquinine anthraquinone-1,4-diyl diether (0.495 g, 0.578 mmol), and potassium osmate dihydrate (0.043 g, 0.117 mmol) in water:tert-butyl alcohol (1:1, 600 mL) cooled to 0° C. was slowly added via an addition funnel a solution of 1-allyl-2-(benzyloxy)-3-tert-butylbenzene (16.2 g, 0.058 mol) in tert-butyl alcohol (50 mL) and the reaction mixture was allowed to stir at 0° C. for 12 h. The reaction mixture was quenched by the addition of sodium sulfite. The reaction mixture was diluted with water (500 mL) and ethyl acetate (500 mL). The aqueous phase was separated and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:2) gave 16.75 g (92%, 32% ee) of (±)-3-[2-(benzyloxy)-3-tert-butylphenyl]propane-1,2-diol as a white solid. mp 79-81° C.; Anal. calcd. for C₂₀H₂₆O₃: C, 76.4; H, 8.33. Found: C, 76.39; H, 8.22.

Intermediate 29 (±)-3-(3-tert-butyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate

Treatment of (±)-3-[2-(benzyloxy)-3-tert-butylphenyl]propane-1,2-diol (16.50 g, 0.053 mol) with p-toluenesulfonyl chloride (10.51 g, 0.055 mol) in pyridine (400 mL) generally according to the procedure described for Intermediate 3 gave 42.84 g (91%) of (±)-3-[2-(benzyloxy)-4-methoxyphen yl]-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the tosylate with palladium on carbon (2.4 g, 10 wt. %) generally according to the procedure described for Intermediate 4 provided 14.71 g (74%) of (±)-3-(3-tert-butyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate as a white solid. mp 98-101° C.; Anal. calcd. for C₂₀H₂₆O₅S: C, 63.47; H, 6.92. Found: C, 63.24; H, 6.99.

Intermediate 30 (±)-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-3-(3-tert-butyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate (14.66 g, 0.039 mol) with triphenylphosphine (11.18 g, 0.043 mol) and diethylazodicarboxylate (7.42 g, 0.043 mol) generally according to the procedure described for Intermediate 5 afforded 12.48 g (89%) of (±)-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C₂₀H₂₄O₄S: C, 66.64; H, 6.71. Found: C, 66.28; H, 6.95.

Intermediate 31 (±)-benzyl (7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Treatment of (±)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (3.25 g, 13.4 mmol) with diisopropylethylamine (4.34 g, 33.6 mmol) and benzyl chloroformate (2.64 g, 15.5 mmol) generally according to the procedure described for Intermediate 12 gave 4.37 g (96%) of (±)-benzyl (7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a white solid. mp 73-76° C.; Anal. Calcd. for C₂₁H₂₅NO₃: C, 74.31; H, 7.42; N, 4.13. Found C, 74.95; H, 7.51; N, 4.18. Chiral HPLC separation of (+)-benzyl (7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol) provided two fractions. Fraction 1 (R_(t)=9.100 min, Chiralcel OJ, ethanol); Fraction 2 (R_(t)=14.428 min, Chiralcel OJ, ethanol).

Intermediate 32 (±)-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of 2-tert-butyl-4-chlorophenol (12.73 g, 0.070 mol) with allyl bromide (10.01 g, 0.083 mol) and potassium carbonate (38.11 g, 0.276 mol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 gave 2-allyl-6-tert-butyl-4-chlorophenol. Treatment of the phenol with 3-chloroperoxybenzoic acid (35.90 g, 0.146 mol, 77%) followed by potassium carbonate (28.18 g, 0.204 mol) generally according to the procedure described for Intermediate 9 provided (±)-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of the alcohol with p-toluenesulfonyl chloride (10.27 g, 0.054 mol) generally according to the procedure described for Intermediate 10 afforded 13.84 g (51%) (±)-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 74-77° C.; Anal. calcd. for C₂₀H₂₃ClO₄S C, 60.83; H, 5.87. Found C, 60.79; H, 5.80.

Intermediate 33 (±)-benzyl (7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Treatment of (±)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine (1.80 g, 6.52 mmol) with diisopropylethylamine (2.11 g, 16.29 mmol) and benzyl chloroformate (1.28 g, 7.49 mmol) generally according to the procedure described for Intermediate 12 gave 2.33 g (95%) of (±)-benzyl (7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C₂₁H₂₄ClNO₃: C, 67.46; H, 6.47; N, 3.75. Found C, 67.27; H, 6.62; N, 3.66. Chiral HPLC separation of (±)-benzyl (7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (R_(t)=5.642 min, Chiralpak AD, hexane:isopropanol 9:1); Fraction 2 (R_(t)=6.494 min, Chiralpak AD, hexane:isopropanol 9:1).

Intermediate 34 (±)-benzyl (7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Treatment of (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylamine (1.03 g, 3.8 mmol) with diisopropylethylamine (0.735 g, 5.7 mmol) and benzyl chloroformate (0.711 g, 4.2 mmol) generally according to the procedure described for Intermediate 12 gave 1.2 g (59%) of (±)-benzyl (7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. R_(f)=0.51 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C₂₂H₂₇NO₄: C, 71.52; H, 7.37; N, 3.79. Found C, 71.2; H, 7.44; N, 3.77.

Intermediate 35 2-(2-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.92 g, 1.12 mmol) and 1,1′-bis(diphenylphosphino) ferrocene (0.62 g, 1.12 mmol) in dioxane (275 mL) was added 2-isopropylphenyl trifluoromethanesulfonate (10.0 g, 37.5 mmol), bis(pinacolato)diboron (10.48 g, 41.26 mmol) and potassium acetate (10.96 g, 55.83 mmol) and the reaction mixture was heated to 90° C. and allowed to stir for 36 h. The reaction mixture was cooled to room temperature and diluted with water (300 mL) and extracted with diethyl ether (2×300 mL). The combined organic layers were washed with water (2×200 mL) and saturated aqueous sodium chloride (200 mL), were dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexane 1:1) provided 3.9 g (43%) of 2-(2-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a pale yellow oil. ¹H NR (DMSO-d₆) δ_(H) 7.57 (d, 1H); 7.38 (t, 1H); 7.30 (d, 1H); 7.13 (t, 1H); 3.57 (m, 1H); 1.27 (s, 12H); 1.14 (d, 6H).

Intermediate 36 (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of 2-allyl-5-bromophenol (27.25 g, 0.128 mmol), with 3-chloroperoxybenzoic acid (66.20 g, 0.384 mol, 77%)) followed by potassium carbonate (44.18 g, 0.319 mol) generally according to the procedure described for Intermediate 9 provided (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol as a yellow oil. Treatment of the oil with p-toluenesulfonyl chloride (15.65 g, 0.082 mol) generally according to the procedure described for Intermediate 10 afforded 24.7 g (78%) of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 90-91° C.; Anal. calcd. for C₁₆H₁₅BrO₄S: C, 50.14; H, 3.94. Found: C, 50.09; H, 3.82.

Intermediate 37 (±)-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.05 g, 5.21 mmol) and phenylboronic acid (0.952 g, 7.81 mmol) in dioxane (50 mL) heated to 100° C. was added dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.205 g, 0.261 mmol) and potassium carbonate (1.80 g, 13.04 mmol) and the reaction mixture was allowed to stir at 100° C. for 12 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether (250 mL), and filtered (celite). The organic layer was washed with water (2×100 mL) and saturated aqueous sodium chloride (100 mL), was dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 1.45 g (73%) of (±)-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a clear oil. R_(f)=0.34 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C₂₂H₂₀O₄S: C, 69.45; H, 5.30. Found: C, 69.17; H, 5.30.

Intermediate 38 (±)-benzyl (4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Treatment of (±)-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (0.622 g, 2.38 mmol) with diisopropylethylamine (0.447 g, 3.57 mmol) and benzyl chloroformate (0.462 g, 2.62 mmol) generally according to the procedure described for Intermediate 12 provided 0.601 g (70%) of (±)-benzyl (4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a white solid. mp 132-134° C.; Anal. calcd. for C₂₃H₂₁NO₃: C, 76.86H, 5.89; N, 3.90. Found: C, 75.98H, 5.80; N, 3.72. Chiral HPLC separation of (±)-benzyl (4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OD, ethanol:water 15:85) provided two fractions. Fraction 1 (R_(t)=6.651 min Chiralcel OD, ethanol:water 1:3); Fraction 2 (R_(t)=7.395 min, Chiralcel OD, ethanol:water 1:3).

Intermediate 39 (±)-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 5.21 mmol), 2-methylphenyl boronic acid (1.06 g, 7.82 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.205 g, 0.261 mmol), and potassium carbonate (1.80 g, 13.04 mmol) generally according to the procedure described for Intermediate 37 provided 1.41 g (69%) of (±)-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. R_(f)=0.42 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C₂₃H₂₂O₄S: C, 70.03; H, 5.62. Found: C, 69.70; H, 5.45.

Intermediate 40 (±)-benzyl[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.533 g, 1.94 mmol) with diisopropylethylamine (0.375 g, 2.90 mmol) and benzyl chloroformate (0.363 g, 2.13 mmol) generally according to the procedure described for Intermediate 12 provided 0.594 g (82%) of (±)-benzyl[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as colorless oil. R_(f)=0.42 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C₂₄H₂₃NO₃: C, 77.19H, 6.21; N, 3.75. Found: C, 76.0H, 6.01; N, 3.55. Chiral HPLC separation of (±)-benzyl[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, methanol) provided two fractions. Fraction 1 (R_(t)=5.952 min Chiralcel OD, methanol); Fraction 2 (R_(t)=7.345 min, Chiralcel OD, methanol).

Intermediate 41 1-allyl-2-(benzyloxy)-3-methoxybenzene

Treatment of guaiacol (25.00 g, 0.201 mol) with allyl bromide (29.24 g, 0.242 mol) and potassium carbonate (83.50 g, 0.604 mol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 afforded 2-allyl-6-methoxyphenol as a brown oil. Treatment of the phenol with potassium carbonate (83.5 g, 0.604 mol), benzyl bromide (36.19 g, 0.212 mol), and tetrabutylammonium iodide (7.42 g, 0.020 mol) generally according to the procedure described for Intermediate 1 gave 23.61 g (45%) of 1-allyl-2-(benzyloxy)-3-methoxybenzene as a pale yellow oil. R_(f)=0.71 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C₁₇H₁₈O₂: C, 80.28; H, 7.13. Found: C, 79.09; H, 6.93.

Intermediate 42 (±)-3-[2-(benzyloxy)-3-methoxyphenyl]propane-1,2-diol

Treatment of (4-methoxy-1,3-benzodioxol-2-yl)methanol (23.61 g, 0.093 mol) with AD-mix-α (129.97 g) generally according to the procedure described for Intermediate 2 provided 26.49 g (99%, 34% ee) of (+)-3-[2-(benzyloxy)-3-methoxyphenyl]propane-1,2-diol as a colorless oil. R_(f)=0.63 (silica, ethyl acetate:hexanes 3:2); Anal. calcd. for C₁₇H₂₀O₄: C, 70.81; H, 6.99. Found: C, 69.33; H, 7.12.

Intermediate 43 (±)-1-[2-(benzyloxy)-3-methoxyphenyl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol

To a solution of (±)-3-[2-(benzyloxy)-3-methoxyphenyl]propane-1,2-diol (50.23 g, 0.174 mol) in N,N-dimethylformamide (600 mL) was added tert-butyldimethylsilyl chloride (28.88 g, 0.192 mol) followed by triethylamine (22.03 g, 0.218 mol) and 4-(dimethylamino)pyridine (2.12 g, 0.017 mol) and the reaction mixture was allowed to stir at room temperature for 6 h. The reaction mixture was quenched by the addition of water (1000 mL) and was extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water (4×300 mL), aqueous hydrogen chloride (1.0 N, 400 mL), saturated aqueous sodium chloride (300 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 58.14 g (83%) of (+)-1-[2-(benzyloxy)-3-methoxyphenyl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol as a colorless oil. R_(f)=0.48 (silica, ethyl acetate:hexanes 3:7); Anal. calcd. for C₂₃H₃₄O₄Si: C, 68.62; H, 8.51. Found: C, 69.20; H, 8.91.

Intermediate 44 (±)-tert-butyl[(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methoxy]dimethylsilane

Treatment of (±)-1-[2-(benzyloxy)-3-methoxyphenyl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol (58.14 g, 0.144 mol) with palladium on carbon (5.81 g, 10 wt. %) generally according to the procedure described for Intermediate 4 provided (+)-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-6-methoxyphenol as a crude oil. Treatment of the phenol with triphenylphosphine (44.52 g, 0.170 mol) and diethylazodicarboxylate (29.56 g, 0.170 mol) generally according to the procedure described for Intermediate 5 gave 34.12 g (80%) of (±)-tert-butyl[(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methoxy]dimethylsilane as a colorless oil. R_(f)=0.67 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C₁₆H₂₆O₃Si: C, 65.26; H, 8.90. Found: C, 64.26; H, 9.24.

Intermediate 45 (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (±)-tert-butyl[(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methoxy]dimethylsilane (34.12 g; 0.116 mol) in tetrahydrofuran (700 mL) cooled to 0° C. was added via an addition funnel tetrabutylammonium fluoride (140 mL, 1.0 M solution in tetrahydrofuran) and the reaction mixture was allowed to stir at room temperature for 6 h. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give (O)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanol, a crude oil. The alcohol was dissolved in dichloromethane (700 mL) and p-toluenesulfonyl chloride (33.14 g, 0.174 mol) was added followed by triethylamine (21.11 g, 0.209 mol) and then 4-(dimethylamino)pyridine (2.12 g, 0.017 mol). The reaction mixture was allowed to stir at 50° C. for 12 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 26.45 g (68%) of (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white crystalline solid. R_(f)=0.38 (silica, ethyl acetate:hexanes 3:7); mp 98-103° C.; Anal. calcd. for C₁₇H₁₈O₅S: C, 61.06; H, 5.43. Found: C, 60.80; H, 5.37.

Intermediate 46 (±)-(7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

To (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (10.00 g, 0.030 mol) was added hydrogen bromide (20 mL, 30 wt. % in acetic acid) and the resulting solution was heated to 40° C. The reaction mixture was allowed to stir at 40° C. for 4 h. The reaction mixture was cooled to room temperature and was diluted with water (250 mL) and extracted with diethyl ether (3×200 mL). The combined organic extracts were washed with saturated sodium bicarbonate (3×300 mL), water (200 mL), and saturated aqueous sodium chloride (200 mL), were dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:3) provided 7.34 g (77%) of (±)-(7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as white solid. R_(f)=0.31 (silica, ethyl acetate:hexanes 1:3); mp 122-125° C.; Anal. calcd. for C₁₆H₁₆O₅S: C, 59.99; H, 5.03. Found: C, 59.8; H, 4.73.

Intermediate 47 (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.00 g, 3.12 mmol) with diisopropylethylamine (0.44 g, 3.43 mmol) and trifluoromethanesulfonic anhydride (0.92 g, 3.28 mmol) generally according to the procedure described for Intermediate 7 gave 1.05 g (74%) of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.45 (silica, ethyl acetate:hexanes 1:3); mp 60-63° C.; Anal. calcd. for C₁₇H₁₅F₃O₇S₂: C, 45.13; H, 3.34. Found: C, 44.85; H, 3.04.

Intermediate 48 (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol

Treatment of 2-allyl-6-bromophenol (61.4 g 0.288 mol) with 3-chloroperoxybenzoic acid (77%, 149.18 g, 0.864 mol)) followed by potassium carbonate (99.56 g, 0.72 mol) generally according to the procedure described for Intermediate 9 provided 49.00 g (78%) (86%) of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol as an amber oil. R_(f)=0.66 (silica, ethyl acetate:hexanes 1:9) ¹H NMR (DMSO-d₆) 8H 7.23 (dd, 1H); 7.14 (dd, 1H); 6.71 (t, 1H); (5.01 m, 1H); 4.85 (m, 1H); 4.99 (m, 2H); 3.36 (d, 2H).

Intermediate 49 (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol (49.0 g, 0.214 mol) with p-toluenesulfonyl chloride (44.9 g, 0.235 mol) generally according to the procedure described for Intermediate 10 gave 66.00 g (80%) (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.44 (silica, ethyl acetate:hexanes 1:4); mp 120-122° C.; Anal. calcd. for C₁₆H₁₅BrO₄S: C, 50.14; H, 3.94. Found: C, 48.47; H, 4.03.

Intermediate 50 (±)-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

To a solution of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.21 mmol) and 3,5-bis(trifluoromethyl)phenylboronic acid (0.86 g, 3.32 mmol) in dioxane (25 mL) heated to 90° C. was added tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 mmol) and potassium phosphate (0.94 g, 4.42 mmol). The reaction mixture was allowed to stir at 90° C. for 12 h. The reaction mixture was allowed to cool and was diluted with diethyl ether (100 mL), filtered (celite), and the solvent was removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethylacetate:hexanes 1:9) afforded 0.75 g (66%) of (±)-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.49 (silica, ethyl acetate:hexanes 1:3); mp 100-105° C.; Anal. calcd. for C₂₄H₁₈F₆O₄S₂: C, 55.82; H, 3.51. Found: C, 55.75; H, 3.35.

Intermediate 51 (±)-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 3-chloro-4-fluorophenylboronic acid (0.87 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.68 g (48%) of (±)-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:3); mp 104-108° C.; Anal. calcd. for C₂₂H₁₈ClFO₄S₂: C, 61.04; H, 4.19. Found: C, 60.74; H, 4.13.

Intermediate 52 (±)-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with phenylboronic acid (0.95 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.40 g (32%) of (±)-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.48 (silica, ethyl acetate:hexanes 1:3); Anal. calcd. for C₂₂H₂₀O₄S-0.2H₂O: C, 68.8; H, 5.35. Found: C, 68.78; H, 5.08.

Intermediate 53 (±)-benzyl (7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Treatment of (±)-benzyl (7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (1.5 g, 1.43 mmol) with diisopropylethylamine (0.277 g, 2.14 mmol) followed by benzyl chloroformate (0.268 g, 1.572 mmol) generally according to the procedure described for Intermediate 12 provided 1.64 (79%) of (±)-benzyl[7-phenyl-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a clear oil. R_(f)=0.68 (silica, ethyl acetate:hexanes 1:2); Anal. calcd. for C₂₃H₂₁NO₃: C, 76.86; H, 5.89; N, 3.90. Found: C, 75.10H, 5.71; N, 3.90. Chiral HPLC separation of (±)-benzyl[7-phenyl-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (R_(t)=10.746 min, Chiralpak AD, ethanol:hexane 1:1); Fraction 2 (R_(t)=13.433 min, Chiralpak AD ethanol:hexane 1:1).

Intermediate 54 (±)-[7-(2-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 2-naphthaleneboronic acid (0.86 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.513 g (36%) of (±)-[7-(2-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.42 (silica, ethyl acetate:hexanes 1:3); Anal. calcd. for C₂₆H₂₂O₄S: C, 72.54; H, 5.15. Found: C, 72.04; H, 5.04.

Intermediate 55 (±)-[7-(3,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 3,5-dichlorophenylboronic acid (0.95 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.22 g (15%) of (±)-[7-(3,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.48 (silica, ethyl acetate:hexanes 1:3); mp 113-115° C.; Anal. calcd. for C₂₂H₁₈Cl₂O₄S: C, 58.8; H, 4.04. Found: C, 58.73; H, 3.77.

Intermediate 56 (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 2-methylphenyl boronic acid (0.266 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.358 g (70%) of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:3); mp 98-100° C.; Anal. calcd. for C₂₃H₂₂O₄S: C, 70.03; H, 5.62. Found: C, 69.83; H, 5.61.

Intermediate 57 (±)-benzyl[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (3.55 g, 12.9 mmol) with diisopropylethylamine (2.5 g, 19.4 mmol) and benzyl chloroformate (2.42 g, 14.2 mmol) generally according to the procedure described for Intermediate 12 provided 4.1 g (85%) of (±)-benzyl[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a clear oil R_(f)=0.64 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C₂₄H₂₃F₄NO₃: C, 77.19; H, 6.21; N, 3.75. Found: C, 76.95; H, 6.18; N, 3.53. Chiral HPLC separation of (±)-benzyl[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, isopropanol:hexane 1:4) provided two fractions. Fraction 1 (R_(t)=7.285 min, isopropanol:hexane 1:4); Fraction 2 (R_(t)=9.361 min, Chiralcel OD, isopropanol:hexane 1:4).

Intermediate 58 (±)-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-thiophene boronic acid (0.334 g, 2.61 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.389 g (77%) of (+j-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow solid. mp 90-92° C.; Anal. calcd. for C₂₀H₁₈O₄S₂: C, 62.15; H, 4.69. Found: C, 62.2; H, 4.72.

Intermediate 59 (±)-benzyl (7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Treatment of (±)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine (0.56 g, 2.09 mmol) with diisopropylethylamine (0.406 g, 3.14 mmol) and benzyl chloroformate (0.393 g, 2.30 mmol) generally according to the procedure described for Intermediate 12 provided 0.54 g (71%) of (±)-benzyl (7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. R_(f)=0.49 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C₂₁H₁₉NO₃S.0.3H₂O: C, 68.01; H, 5.33; N, 3.78. Found: C, 67.88; H, 5.18; N, 3.72. Chiral HPLC separation of (±)-benzyl (7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel AD, water:methanol 1:9) provided two fractions. Fraction 1 (R_(t)=13.00 min, (Chiralcel AD, water:methanol 1:9); Fraction 2 (R_(t)=14.1 min, (Chiralcel AD, water:methanol 1:9).

Intermediate 60 (±)-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 2-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.422 g (81%) of (±)-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. mp 99-101° C.; Anal. calcd. for C₂₂H₁₉FO₄S: C, 66.32; H, 4.81. Found: C, 65.16; H, 4.86.

Intermediate 61 (±)-benzyl[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.5 g, 5.36 mmol) with diisopropylethylamine (1.04 g, 8.04 mmol) and benzyl chloroformate (1.01 g, 5.89 mmol) generally according to the procedure described for Intermediate 12 afforded 1.7 g (84%) of (±)-benzyl[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil R_(f)=0.68 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C₂₂H₁₈FNO₃: C, 72.72; H, 4.99; N, 3.85. Found: C, 72.65H, 5.41; N, 3.47. Chiral HPLC separation of (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (R_(t)=13.628 min, Chiralcel OJ, hexane:isopropanol 9:1); Fraction 2 (R_(t)=17.247 min, Chiralcel OJ, hexane:isopropanol 9:1).

Intermediate 62 (±)-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (10.00 g, 26.10 mmol) with 2-(trifluoromethy)phenylboronic acid (7.43 g, 39.14 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.786 g, 1.3 mmol), and potassium carbonate (9.01 g, 65.19 mmol) generally according to the procedure described for Intermediate 37 afforded 8.46 g (72%) of (±)-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a tan solid. mp 116-118° C.; Anal. calcd. for C₂₃H₁₉F₃O₄S: C, 61.6; H, 4.27. Found: C, 61.91; H, 4.23.

Intermediate 63 (±)-benzyl {7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate

Treatment of (±)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (0.813 g, 2.46 mmol) with diisopropylethylamine (0.478 g, 3.69 mmol) and benzyl chloroformate (0.462 g, 2.71 mmol) generally according to the procedure described for Intermediate 12 gave 0.99 g (94%) of (±)-benzyl {7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate as a pale yellow oil R_(f)=0.60 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C₂₄H₂₀F₃NO₃: C, 67.44; H, 4.71; N, 3.15. Found: C, 67.43H, 4.76; N, 3.15. Chiral HPLC separation of (±)-benzyl[7-(2-(trifluoromethyl))-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, isopropanol:carbon dioxide 3:17) provided two fractions. Fraction 1 (R_(t)=5.252 min, Chiralcel OJ, isopropanol:carbon dioxide 3:17); Fraction 2 (R_(t)=6.280 min, Chiralcel OJ, isopropanol:carbon dioxide 3:17).

Intermediate 64 (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.00 g, 2.61 mmol) with 2,6-dimethylphenylboronic acid (0.783 g, 5.22 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.103 g, 0.135 mmol), and potassium carbonate (0.90 g, 6.52 mmol) generally according to the procedure described for Intermediate 37 provided 0.192 g (18%) of (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C₂₄H₂₄O₄S: C, 70.56; H, 5.92. Found: C, 68.01; H, 5.6.

Intermediate 65 (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.947 g, 3.73 mmol) with diisopropylethylamine (0.725 g, 5.60 mmol) and benzyl chloroformate (0.7647 g, 4.48 mmol) generally according to the procedure described for Intermediate 12 gave 1.26 g (87%) of (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil R_(f)=0.56 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C₂₅H₂₅NO₃: C, 77.49; H, 6.50; N, 3.61. Found: C, 77.42H, 6.57; N, 3.62. Chiral HPLC separation of (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, methanol:carbon dioxide 4:6) provided two fractions. Fraction 1 (R_(t)=2-89 min, Chiralcel OJ, methanol:carbon dioxide 4:6); Fraction 2 (R_(t)=3.84 min, Chiralcel OJ, methanol:carbon dioxide 4:6).

Intermediate 66 (±)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.31 mmol) with 2-methoxyphenylboronic acid (0.297 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 gave 0.399 g (74%) of (+)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a tan solid. mp 100-103° C.; Anal. calcd. for C₂₃H₂₂O₅S: C, 67.3; H, 5.4. Found: C, 66.95; H, 5.43.

Intermediate 67 (±)-benzyl[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.296 g, 1.01 mmol) with diisopropylethylamine (1.52 g, 1.5 mmol) and benzyl chloroformate (0.190 g, 1.11 mmol) generally according to the procedure described for Intermediate 12 afforded 0.33 g (84%) (±)-benzyl[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate of a colorless oil R_(f)=0.72 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C₂₄H₂₃NO₄: C, 74.02; H, 5.95; N, 3.6. Found: C, 73.68H, 5.81; N, 3.43.

Intermediate 68 (±)-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 2-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.380 g (70%) of (±)-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a tan solid. mp 100-103° C.; Anal. calcd. for C₂₂H₁₉ClO₄S: C, 63.69; H, 4.62. Found: C, 63.43; H, 4.69.

Intermediate 69 (±)-benzyl[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.743 g 2.52 mmol) with diisopropylethylamine (0.488 g, 3.77 mmol) and benzyl chloroformate (0.472 g, 2.77 mmol) generally according to the procedure described for Intermediate 12 afforded 0.749 g (76%) (+)-benzyl[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a white solid. mp 155-157° C.; Anal. calcd. for C₂₃H₂₀ClNO₃: C, 70.14; H, 5.12; N, 3.56. Found: C, 70.1; H, 5.15; N, 3.37. Chiral HPLC separation of (±)-benzyl[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:ethanol 1:1) provided two fractions. Fraction 1 (R_(t)=9.655 min, Chiralcel OJ, hexane:ethanol 1:1); Fraction 2 (R_(t)=16.300 min, Chiralcel OJ, hexane:ethanol 1:1).

Intermediate 70 (±)-benzyl[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine (1.69 g, 5.56 mmol) with diisopropylethylamine (1.08 g, 8.34 mmol) and benzyl chloroformate (1.04 g, 6.12 mmol) generally according to the procedure described for Intermediate 12 gave 1.92 (89%) of (+)-benzyl[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a yellow oil. R_(f)=0.66 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C₂₆H₂₇NO₃: C, 77.78; H, 6.78; N, 3.49. Found: C, 77.5; H, 6.7; N, 3.33. Chiral HPLC separation of (±)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (R_(t)=8.131 min, Chiralcel OD, hexane:isopropanol 9:1); Fraction 2 (R_(t)=11.048 min, Chiralcel OD, hexane:isopropanol 9:1).

Intermediate 71 (±)-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 3-methylbenzeneboronic (0.68 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.899 g (69%) of (±)-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.44 (silica, ethyl acetate:hexanes 1:3); mp 81-82° C.; Anal. calcd. for C₂₃H₂₂O₄S.0.2H₂O: C, 69.39; H, 5.67. Found: C, 69.42; H, 5.49.

Intermediate 72 (±)-benzyl[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.76 g, 6.38 mmol) with diisopropylethylamine (2.47 g, 19.17 mmol) followed by benzyl chloroformate (1.19 g, 7.02 mmol) generally according to the procedure described for Intermediate 12 provided 1.4 g (58%) of (±)-benzyl[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a clear oil. R_(f)=0.68 (silica, ethyl acetate:hexanes 1:2); Anal. calcd. for C₂₄H₂₃NO₃: C, 77.19; H, 6.20; N, 3.75. Found: C, 76.88H, 6.25; N, 3.51. Chiral HPLC separation of (±)-benzyl[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (R_(t)=10.439 min, Chiralpak AD, ethanol:hexane 1:1); Fraction 2 (R_(t)=11.833 min, Chiralpak AD ethanol:hexane 1:1).

Intermediate 73 (±)-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.392 g (75%) of (±)-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid. mp 88-90° C.; Anal. calcd. for C₂₂H₁₉FO₄S: C, 66.32; H, 4.81. Found: C, 65.63; H, 4.84.

Intermediate 74 (±)-benzyl[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.798 g, 2.856 mmol) with diisopropylethylamine (0.554 g, 4.286 mmol) and benzyl chloroformate (0.536 g, 3.143 mmol) generally according to the procedure described for Intermediate 12 afforded 1.01 g (94%) of (±)-benzyl[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a white solid. R_(f)=0.40 (silica, ethyl acetate:hexanes 1:4); Anal. Calcd. for C₂₃H₂₀FNO₃: C, 73.2; H, 5.34; N, 3.71. Found: C, 92.96; H, 5.38; N, 3.59.

Intermediate 75 (±)-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.404 g (75%) of (+)-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid. mp 101-103° C.; Anal. calcd. for C₂₂H₁₉ClO₄S: C, 63.69; H, 4.62. Found: C, 63.59; H, 4.52.

Intermediate 76 (±)-benzyl[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.6 g, 5.4 mmol) with diisopropylethylamine (1.197 g, 9.26 mmol) and benzyl chloroformate (1.02 g, 5.96 mmol) generally according to the procedure described for Intermediate 12 afforded 1.59 g (75%) of (±)-benzyl[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. R_(f)=0.56 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C₂₃H₂₀ClNO₃: C, 70.14; H, 5.12; N, 3.56. Found: C, 69.11; H, 5.07; N, 3.37. Chiral HPLC separation of (±)-benzyl[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (R_(t)=15.935 min Chiralcel OD, hexane:isopropanol 9:1); Fraction 2 (R_(t)=18.546 min, Chiralcel OD, hexane:isopropanol 9:1).

Intermediate 77 (±)-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 13.04 mmol) with 3-methoxyphenylboronic acid (2.97 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.512 g, 0.652 mmol) and potassium carbonate (4.51 g, 32.62 mmol) generally according to the reaction conditions described for Intermediate 37 gave 4.48 g (84%) of (±)-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 141-142° C.; Anal. calcd. for C₂₃H₂₂O₅S: C, 67.3; H, 5.4. Found: C, 66.51; H, 5.41.

Intermediate 78 (±)-benzyl[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.4 g, 9.4 mmol) with diisopropylethylamine (1.82 g, 14.10 mmol) and benzyl chloroformate (1.92 g, 11.28 mmol) generally according to the reaction conditions described for Intermediate 12 afforded 3.42 g (93%) of (±)-benzyl[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. R_(f)=0.78 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C₂₄H₂₃NO₄: C, 74.02; H, 5.95; N, 3.6. Found: C, 73.52; H, 6.06; N, 3.28.

Intermediate 79 (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-(trifluoromethyl)phenylboronic acid (0.372 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.383 g (65%) of (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. mp 90-93° C.; Anal. calcd. for C₂₃H₁₉F₃O₄S: C, 61.6; H, 4.27. Found: C, 61.52; H, 4.21.

Intermediate 80 (±)-benzyl {7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate

Treatment of (±)-[7-(3-trifluoromethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.67 g, 5.06 mmol) with diisopropylethylamine (0.98 g, 7.59 mmol) and benzyl chloroformate (1.04 g, 6.07 mmol) generally according to the procedure described for Intermediate 12 provided 2.1 g (97%) of (±)-benzyl {7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl)}methylcarbamate as a colorless oil. R_(f)=0.51; Anal. calcd. for C₂₄H₂₀F₃NO₃: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.08; H, 5.05; N, 3.22.

Intermediate 81 (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (11.2 g, 29.22 mmol) with 4-methylphenylboronic acid (5.96 g, 43.84 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (1.148 g, 1.46 mmol), and potassium carbonate (10.10 g, 73.07 mmol) generally according to the procedure described for Intermediate 37 afforded 9.8 g (85%) of (+)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate a white solid. mp 145-147° C.; Anal. calcd. for C₂₃H₂₂O₄S: C, 70.03; H, 5.62. Found: C, 69.91; H, 5.70.

Intermediate 82 (±)-benzyl[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.385 g, 1.396 mmol) with diisopropylethylamine (0.270 g, 2.09 mmol) and benzyl chloroformate (0.285 g, 1.675 mmol) generally according to the procedure described for Intermediate 12 provided 0.483 g (93%) of (+)-benzyl[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as colorless oil. R_(f)=0.47 (silica, ethyl acetate:hexane 2:8); mp 83-86° C.; Anal. calcd. for C₂₄H₂₃NO₃: C, 77.19; H, 6.21; N, 3.75. Found: C, 76.97; H, 5.99; N, 3.68. Chiral HPLC separation of (±)-benzyl[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak OD, methanol:carbon dioxide 1:1) provided two fractions. Fraction 1 (R_(t)=3.788 min Chiralpak OD, methanol:carbon dioxide 1:1); Fraction 2 (R_(t)=4.398 min, Chiralpak OD, methanol:carbon dioxide 1:1).

Intermediate 83 (±)-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (3.0 g, 7.82 mmol) with 4-methoxyphenylboronic acid (1.78 g, 11.74 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.307 g, 0.391 mmol), and potassium carbonate (2.70 g, 19.57 mmol) generally according to the procedure described for Intermediate 37 provided 2.2 g (68%) of (±)-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. mp 116-117° C.; Anal. calcd. for C₂₃H₂₂O₅S: C, 67.30; H, 5.40. Found: C, 67.31; H, 5.35.

Intermediate 84 (±)-benzyl[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of 1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.727 g, 2.49 mmol) with diisopropylethylamine (0.483 g, 3.73) and benzyl chloroformate (0.510 g, 2.99 mmol) generally according to the procedure described for Intermediate 12 provided 0.820 g of (+)-benzyl[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. R_(f)=0.48 (silica, ethyl acetate:hexanes 1:5); Anal. calcd. for C₂₄H₂₃NO₄: C, 74.02; H, 5.95; N, 3.60. Found: C, 73.66H, 6.13; N, 3.42. Chiral HPLC separation of (±)-benzyl[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel AD, methanol) provided two fractions. Fraction 1 (R_(t)=7.386 min, Chiralcel AD, methanol); Fraction 2 (R_(t)=10.882 min, Chiralcel AD, methanol).

Intermediate 85 (±)-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-(trifluoromethyl)phenylboronic acid (0.372 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.435 g (74%) of (±)-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a light yellow solid. mp 116-118° C.; Anal. calcd. for C₂₃H₁₉F₃O₄S: C, 61.6; H, 4.27. Found: C, 61.37; H, 4.36.

Intermediate 86 (±)-benzyl {7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate

Treatment of (±)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (1.8 g, 6.14 mmol) with diisopropylethylamine (1.06 g, 8.20) and benzyl chloroformate (1.12 g, 6.56 mmol) generally according to the procedure described for Intermediate 12 afforded 2.38 g (91%) of (+)-benzyl {7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate as a white solid. R_(f)=0.48 (silica, ethyl acetate:hexanes 1:4); mp 100-102° C.; Anal. calcd. for C₂₄H₂₀F₃NO₃: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.37; H, 4.69; N, 3.15.

Intermediate 87 (±)-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.408 g (78%) of (±)-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid. mp 83-86° C.; Anal. calcd. for C₂₂H₁₉FO₄S: C, 66.32; H, 4.81. Found: C, 66.11; H, 4.61.

Intermediate 88 (±)-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.367 g (68%) of (±)-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as an orange solid. mp 130-133° C.; Anal. calcd. for C₂₂H₁₉ClO₄S: C, 63.69; H, 4.62. Found: C, 62.82; H, 4.56.

Intermediate 89 (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2,4-dichlorophenylboronic acid (3.73 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 4.5 g (75%) of (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C₂₂H₁₈Cl₂O₄S: C, 58.8; H, 4.04. Found: C, 59.01; H, 4.09.

Intermediate 90 (±)-benzyl[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.9 g, 5.75 mmol) with diisopropylethylamine (1.11 g, 8.62) and benzyl chloroformate (1.18 g, 6.89 mmol) generally according to the procedure described for Intermediate 12 afforded 2.14 g (87%) of (±)-benzyl[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a white solid. mp 87-89° C.; Anal. calcd. for C₂₃H₁₉Cl₂NO₃: C, 64.5; H, 4.47; N, 3.27. Found: C, 64.65; H, 4.78; N, 3.08.

Intermediate 91 (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]propane-1,2-diol

Treatment of 4-chloro-2-methoxyphenol (30.0 g, 0.19 mol) with sodium hydride (9.1 g, 0.23 mol, 60 wt. %) and allyl bromide (27.46 g, 0.23 mol) followed by treatment of the resultant allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 gave 2-allyl-4-chloro-6-methoxyphenol as a yellow oil. Treatment of 2-allyl-4-chloro-6-methoxyphenol with sodium hydride (7.08 g, 0.177 mol, 60 wt. %) and benzyl bromide (30.27 g, 0.177 mol) generally according to the procedure described for Intermediate 13 provided 1-allyl-2-(benzyloxy)-5-chloro-3-methoxybenzene as a pale yellow oil. Treatment of the olefin (35.5 g, 0.123 mol) of with AD-mix-α (132.0 g) generally according to the procedure described for Intermediate 2 gave 35 g (54%) of (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]propane-1,2-diol as a white solid. mp. 65-68° C. Anal. calcd. for C₁₇H₁₉ClO₄: C, 63.26; H, 5.93. Found: C, 65.29; H, 6.23.

Intermediate 92 (±)-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]-1,2-propanediol (32 g, 0.1 mol) with p-toluenesulfonyl chloride (21 g, 0.11 mol) in pyridine generally according to the procedure described for intermediate 3 provided (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the tosylate with palladium on carbon (2.32 g, 5 wt. %) generally according to the procedure described for Intermediate 4 afforded (±)-3-(5-chloro-2-hydroxy-3-methoxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the phenol with triphenylphosphine (23.6 g, 0.09 mol) and diisopropyl azodicarboxylate (18.2 g, 0.09 mol) generally according to the procedure described for Intermediate 5 afforded 28 g (76%) of (±)-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a pale yellow solid. mp 99-102° C.; Anal. calcd. for C₁₇H₁₇ClO₅S: C, 55.36; H, 4.65. Found: C, 55.35; H, 4.62.

Intermediate 93 (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (22.1 g, 0.06 mol) with hydrogen bromide (400 mL, 30 wt. % in acetic acid) generally according to the procedure described for Intermediate 46 gave 14.6 g of (±)-(5-chloro-7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(5-chloro-7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.5 g, 12.68 mmol) with trifluoromethanesulfonic anhydride (2.34 mL, 13.9 mmol) and diisopropylethylamine (2.43 mL, 13.9 mmol) generally according to the procedure described for Intermediate 7 provided 6.27 g (99%) of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a light yellow solid. mp 55-57° C.; Anal. calcd. for C₁₇H₁₄ClF₃O₇S₂: C, 41.94; H, 2.90. Found: C, 42.10; H, 2.76.

Intermediate 94 (±)-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.10 mmol) with phenyl boronic acid (0.564 g, 4.60 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.252 g, 0.30 mmol), and potassium carbonate (0.829 g, 6.0 mmol) generally according to the procedure described for Intermediate 35 provided 0.94 g of a white paste. Re-crystallization from methanol afforded 0.6 g (47%) of (±)-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 127-130° C.; Anal. calcd. for C₂₂H₁₉ClO₄S: C, 63.69; H, 4.62. Found: C, 62.51; H, 4.48.

Intermediate 95 (±)-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.10 mmol) with 3-chlorophenylboronic acid (0.72 g, 4.60 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.252 g, 0.30 mmol), and potassium carbonate (0.829 g, 6.0 mmol) generally according to the procedure described for Intermediate 35 gave 1.1 g (80%) of (±)-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 80-82° C. Anal. calcd. for C₂₂H₁₈Cl₂O₄S: C, 58.8; H, 4.04. Found: C, 56.91; H, 3.82.

Intermediate 96 (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.10 mmol) with thiophene-3-boronic acid (0.62 g, 4.88 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.265 g, 0.325 mmol), and potassium carbonate (0.898 g, 6.5 mmol) generally according to the procedure described for Intermediate 35 provided 0.22 g (17%) of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 115-117° C.; Anal. calcd. for C₂₀H₁₇ClO₄S₂: C, 57.07; H, 4.07. Found: C, 56.17; H, 3.85.

Intermediate 97 (±)-2-(azidomethyl)-5-chloro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran

Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.10 mmol) with 3-methylphenylboronic acid (0.63 g, 4.60 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.252 g, 0.30 mmol), and potassium carbonate (0.829 g, 6.0 mmol) generally according to the procedure described for Intermediate 35 gave (±)-[5-chloro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of the tosylate with sodium azide (0.31 g, 4.78 mmol) generally according to the procedure described for Intermediate 98 afforded 0.32 g (34%) of (±)-2-(azidomethyl)-5-chloro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran as a tan solid. mp 48-50° C.; Anal. calcd. for C₁₆H₁₄ClN₃O: C, 64.11; H, 4.71; N, 14.02. Found: C, 62.95; H, 4.62; N, 13.72.

Intermediate 98 (±)-2-(azidomethyl)-5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran

To a solution of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.5 g, 10.69 mmol) in dimethylsulfoxide (150 mL) was added sodium azide (3.6 g, 55.38 mmol) and the reaction mixture was heated to 70° C. and allowed to stir for 6 h. The reaction mixture was cooled to room temperature and diluted with water (300 mL) and diethyl ether (200 mL). The aqueous layer was separated and extracted with diethyl ether (200 mL). The combined organic layers were washed with water (3×200 mL), saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent removed in vacuo to afford 2.6 g (83%) of (±)-2-(azidomethyl)-5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran as a white solid. mp 50-52° C.; Anal. calcd. for C₁₃H₁₀ClN₃OS: C, 53.52; H, 3.45; N, 14.40. Found: C, 53.50; H, 3.33; N, 14.26.

Intermediate 99 (±)-benzyl (5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate

Treatment of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.45 g, 8.11 mmol) with benzyl chloroformate (2.07 g, 12.15 mmol) and diisopropylethylamine (3.43 g, 24.32 mmol) generally according to the procedure described for Intermediate 12 provided 2.6 g (81%) of (±)-benzyl (5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a white solid. mp 90-92° C.; Anal. calcd. for C₂₁H₁₈ClNO₃S: C, 63.07; H, 4.54; N, 3.50. Found: C, 63.44; H, 4.51; N, 3.43. Chiral HPLC separation of (±)-benzyl (5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, hexane:ethanol 1:1) provided two fractions. Fraction 1 (R_(t)=11.538 min, (Chiralpak AD, hexane:ethanol 1:1); Fraction 2 (R_(t)=17.694 min, (Chiralpak AD, hexane:ethanol 1:1).

Intermediate 100 2-(allyloxy)-1-bromo-4-fluorobenzene

Treatment of 2-bromo-5-fluorophenol (10.00 g, 0.052 mol) with potassium carbonate (29.30 g, 0.209 mol) and allyl bromide (7.60 g, 0.063 mol) generally according to the reaction procedure described for Intermediate 8 provided 12.1 g (99%) of 2-(allyloxy)-1-bromo-4-fluorobenzene as a colorless oil. R_(f)=0.37 (silica, ethyl acetate:hexanes 1:9); ¹H NMR (DMSO-d₆) δ_(H) 7.58 (dd, 1H); 7.05 (dd, 1H); 6.75 (dt, 1H); 6.02 (m, 1H); 5.43 (d, 1H); 5.27 (d, 1H); 4.65 (m, 2H).

Intermediate 101 2-allyl-6-bromo-3-fluorophenol

Treatment of 2-(allyloxy)-1-bromo-4-fluorobenzene (12.00 g, 0.052 mol) in refluxing mesitylene generally according to the reaction procedure described for Intermediate 8 provided 11.5 g (95%) of 2-allyl-6-bromo-3-fluorophenol as a pale yellow oil. R_(f)=0.48 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C₉H₈BrFO: C, 46.78; H, 3.49. Found: C, 47.59; H, 3.47.

Intermediate 102 (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol

Treatment of 2-allyl-6-bromo-3-fluorophenol (9.01 g, 0.039 mol) with 3-chloroperoxybenzoic acid (77%, 13.46 g, 0.06 mol) followed by potassium carbonate (13.82 g, 0.10 mol) generally according to the reaction procedure described for Intermediate 9 gave 6.71 g (70%) of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. R_(f)=0.20 (silica, ethyl acetate:hexanes 1:4); mp 40-43° C.; Anal. calcd. for C₉H₈BrFO₂.0.2H₂O: C, 43.13; H, 3.38. Found: C, 42.94; H, 3.15.

Intermediate 103 (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol (6.21 g, 0.025 mol) with p-toluenesulfonyl chloride (5.26 g, 0.028 mol) in pyridine (120 mL) generally according to the procedure described for Intermediate 10 afforded 8.85 g (88%) of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.60 (silica, ethyl acetate:hexanes 1:1); mp 100-103° C.; Anal. calcd. for C₁₆H₁₄BrFO₄S: C, 47.89; H, 3.52. Found: C, 47.89; H, 3.68.

Intermediate 104 (±)-(4-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 4.98 mmol) with phenyl boronic acid (0.91 g, 7.22 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.392 g, 0.498 mmol), and potassium carbonate (1.72 g, 12.46 mmol) according to the procedure described for Intermediate 37 gave 1.07 g (54%) of (±)-(4-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.46 (silica, ethyl acetate:hexanes 1:4); ¹H NMR (DMSO-d₆) δ_(H) 7.70 (d, 2H); 7.53 (d, 2H); 7.40 (t, 2H); 7.32 (m, 4H); 6.77 (t, 1H); 5.15 (m, 1H); 4.31 (dd, 1H); 4.22 (dd, 1H); 3.30 (dd, 1H, obscured by H₂O peak); 3.01 (dd, 1H).

Intermediate 105 (±)-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.05 g, 5.11 mmol) with 2-methylphenyl boronic acid (1.04 g, 7.66 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.201 g, 0.255 mmol), and potassium carbonate (1.77 g, 12.77 mmol) generally according to the procedure described for Intermediate 37 provided 1.38 g (65%) of (±)-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.34 (silica, ethyl acetate:hexanes 1.5:8.5); Anal. calcd. for C₂₃H₂₁FO₄S: C, 66.97; H, 5.13. Found: C, 66.95; H, 4.76.

Intermediate 106 2-allyl-6-bromo-4-fluorophenol

Treatment of 1-(allyloxy)-2-bromo-4-fluorobenzene (23.90 g, 0.103 mol) in refluxing mesitylene (50 mL) generally according to the procedure described for Intermediate 8 provided 23.44 g (99%) 2-allyl-6-bromo-4-fluorophenol as a brown oil. R_(f)=0.64 (silica, ethyl acetate:hexanes 1:19); Anal. calcd. for C₉H₈BrFO: C, 46.78; H, 3.49. Found: C, 49.19; H, 3.59.

Intermediate 107 (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol

Treatment of 2-allyl-6-bromo-4-fluorophenol (25.1 g, 0.109 mol) with 3-chloroperoxybenzoic acid (77%, 56.24 g, 0.326 mol) followed by potassium carbonate (62.19 g, 0.45 mol) generally according to the procedure described for Intermediate 9 provided 20.98 g (78%) of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. R_(f)=0.54 (silica, ethyl acetate:hexanes 1:1); mp 53-57° C.; Anal. calcd. for C₉H₈BrFO₂.0.1C₄H₈O₂: C, 44.13; H, 3.47. Found: C, 44.17; H, 3.16.

Intermediate 108 (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol (11.5 g, 0.047 mol) with p-toluenesulfonyl chloride (9.76 g, 0.051 mol) generally according to the procedure described for Intermediate 10 gave 12.50 g (66%) (O)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.44 (silica, ethyl acetate:hexanes 1:4); mp 84-86° C.; Anal. calcd. for C₁₆H₁₄BrFO₄S: C, 47.89; H, 3.52. Found: C, 47.65; H, 3.63.

Intermediate 109 (±)-(5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with phenyl boronic acid (0.912 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 gave 1.62 g (82%) of (±)-(5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow oil. R_(f)=0.54 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C₂₂H₁₉FO₄S.0.2C₄H₈O₂: C, 65.82; H, 4.99. Found: C, 65.77; H, 4.99.

Intermediate 110 (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with 2-methylphenyl boronic acid (1.017 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 provided 1.58 g (77%) of (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. R_(f)=0.47 (silica, ethyl acetate:hexanes 3:17); Anal. calcd. for C₂₂H₁₉FO₄S.0.2C₄H₈O₂: C, 66.46; H, 5.30. Found: C, 66.25; H, 4.98.

Intermediate 111 (±)-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with 2-chlorophenyl boronic acid (1.17 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 afforded 1.44 g (67%) of (±)-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.26 (silica, ethyl acetate:hexanes 3:17); Anal. calcd. for C₂₂H₁₈ClFO₄S: C, 61.04; H, 4.19. Found: C, 61.02; H, 3.95.

Intermediate 112 (±)-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with 2-fluorophenyl boronic acid (1.05 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 gave 1.94 g (94%) of (±)-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. R_(f)=0.38 (silica, ethyl acetate:hexanes 3:17); Anal. calcd. for C₂₂H₁₈F₂O₄S: C, 63.45; H, 4.36. Found: C, 63.13; H, 4.19.

Intermediate 113 (±)-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.01 g, 10.0 mmol) with 2-(trifluoromethyl)-phenyl boronic acid (2.85 g, 15.0 mmol), dichlorobis(tri-o-tolylphosphine)palladium(1) (0.786 g, 1.00 mmol), and potassium carbonate (3.46 g, 25.00 mmol) generally according to the procedure described for Intermediate 37 provided 4.34 g (93%) of (±)-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow oil. R_(f)=0.54 (silica, ethyl acetate:hexanes 3:7); Anal. calcd. for C₂₃H₁₈F₄O₄S: C, 59.22; H, 3.89. Found: C, 60.19; H, 4.29.

Intermediate 114 (±)-benzyl[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (3.11 g, 12.1 mmol) with diisopropylethylamine (2.34 g, 18.1 mmol) and benzyl chloroformate (2.27 g, 13.3 mmol) generally according to the procedure described for Intermediate 12 gave 4.35 (92%) of (±)-benzyl[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. R_(f)=0.83 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C₂₄H₂₂FO₃.0.2H₂O: C, 72.97; H, 5.72; N, 3.55. Found: C, 72.8; H, 5.72; N, 3.48. Chiral HPLC separation of (+)-benzyl[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 8:2) provided two fractions. Fraction 1 (R_(t)=7.269 min, Chiralcel OD, hexane:isopropanol 8:2); Fraction 2 (R_(t)=8.449 min, Chiralcel OD, hexane:isopropanol 8:2).

Intermediate 115 (±)-benzyl[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate

Treatment of (±)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.92 g, 10.5 mmol) with diisopropylethylamine (1.70 g, 13.1 mmol) and benzyl chloroformate (1.97 g, 11.6 mmol) generally according to the procedure described for Intermediate 12 provided 3.02 (70%) of (±)-benzyl[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. R_(f)=0.76 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C₂₃H₁₉ClFNO₃.0.5H₂O: C, 65.64; H, 4.79; N, 3.33. Found: C, 65.28; H, 4.73; N, 3.18. Chiral HPLC separation of (±)-benzyl[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:ethanol 1:1) provided two fractions. Fraction 1 (R_(t)=9.322 min, Chiralcel OJ, hexane:ethanol 1:1); Fraction 2 (R_(t)=13.646 min, Chiralcel OJ, hexane:ethanol 1:1).

Intermediate 116 (±)-benzyl {5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate

Treatment of (±)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (1.87 g, 5.38 mmol) with diisopropylethylamine (1.74 g, 13.4 mmol) and benzyl chloroformate (1.01 g, 5.92 mmol) following the procedure described for Intermediate 12 provided 2.03 (85%) of (±)-benzyl {5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate as a white solid. R_(f)=0.69 (silica, ethyl acetate:hexanes 1:9); mp 76-80° C.; Anal. calcd. for C₂₄H₁₉F₄NO₃: C, 64.72; H, 4.3; N, 3.14. Found: C, 65.01; H, 4.3; N, 2.99.

Intermediate 117 (±)-(7-bromo-4,5-difluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of 2-allyl-6-bromo-3,4-difluorophenol (5.0 g, 0.020 mol) with 3-chloroperoxybenzoic acid (77%, 8.1 g, 0.036 mol) followed by potassium carbonate (6.94 g, 0.050 mol) generally according to the procedure described for Intermediate 9 afforded (+)-(7-bromo-4,5-difluoro-2,3-dihydro-1-benzofuran-2-yl)methanol a brown oil. Treatment of the alcohol with diisopropylethylamine (2.57 g, 0.020 mol), p-toluenesulfonyl chloride (2.28 g, 0.012 mol), and 4-(dimethylamino)pyridine (0.29 g, 2.375 mmol) generally according to the procedure described for Intermediate 45 gave 2.9 g (35%) of (±)-(7-bromo-4,5-difluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.46 (silica, ethyl acetate:hexanes 1:3); ¹H NMR (DMSO-d₆) δ_(H) 7.73 (d, 2H); 7.50 (dd, 1H); 7.43 (d, 2H); 5.15 (m, 1H); 4.3 (dd, 1H); 4.22 (dd, 1H); 3.45 (dd, 1H); 3.08 (dd, 1H).

Intermediate 118 (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (±)-(7-bromo-4,5-difluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.59 mmol) in dioxane (30 mL) was added phenylboronic acid (0.656 g, 5.38 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.293 g, 0.359 mmol), and potassium carbonate (0.993 g, 7.18 mmol) and the reaction mixture was heated at reflux for 48 h. The reaction mixture was filtered (celite), rinsed (ethyl acetate), and the combined organic layers were washed with water (100 mL), aqueous sodium chloride (75 mL), dried (sodium sulfate) and the solvent was removed in vacuo to provide a crude solid. Purification by column chromatography (silica, ethyl acetate:hexane 1:9) afforded 1.19 g (80%) of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.76 (silica, ethyl acetate:hexanes 1:9); ¹H NMR (DMSO-d₆) δ_(H) 7.69 (d, 2H); 7.50 (dd, 1H); 7.56 (d, 2H); 7.35 (m, 6H); 5.14 (m, 1H); 4.30 (dd, 1H); 4.20 (dd, 1H); 3.39 (dd, 1H); 3.05 (dd, 1H).

Intermediate 119 (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide

To a solution of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.40 mmol) in N,N-dimethylformamide (25 mL) was added sodium azide (0.781 g, 12.02 mmol) and the reaction mixture was heated to 70° C. and allowed to stir for 3 h. The reaction mixture was allowed to cool and the solvent was removed in vacuo to provide a crude solid. The residue was suspended in ethyl acetate (100 mL) and washed with water (50 mL) and aqueous sodium chloride (50 mL), was dried (sodium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 0.68 g (99%) of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide as a white solid. R_(f)=0.93 (silica, ethyl acetate:hexanes 1:9); ¹H NMR (DMSO-d₆) δ_(H) 7.65 (d, 2H); 7.41 (m, 3H); 7.31 (t, 1H); 5.15 (m, 1H); 3.64 (m, 2H); 3.46 (dd, 1H); 3.10 (dd, 1H).

Intermediate 120 (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-4,5-difluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.59 mmol) with 2-methylphenyl boronic acid (0.732 g, 5.38 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.293 g, 0.359 mmol), and potassium carbonate (0.993 g, 7.18 mmol) generally according to the procedure described for Intermediate 118 afforded 1.3 g (84%) of (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.72 (silica, ethyl acetate:hexanes 1:4); ¹H NMR (DMSO-d₆) δ_(H) 7.67 (d, 2H); 7.38 (d, 2H); 7.20 (m, 3H); 7.05 (m, 2H); 5.05 (m, 1H); 4.22 (dd, 2H); 4.13 (dd, 1H); 3.40 (dd, 1H); 3.02 (dd, 1H); 2.05 (s, 3H).

Intermediate 121 (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide

Treatment of (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.3 g, 3.02 mmol) with sodium azide (0.983 g, 15.11 mmol) generally according to the procedure described for intermediate 98 gave 0.82 g (90%) of (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide as a colorless oil. R_(f)=0.69 (silica, ethyl acetate:hexanes 1:4); ¹H NMR (DMSO-d₆) δ_(H) 7.25 (d, 2H); 7.14 (m, 3H); 5.06 (m, 1H); 3.67 (dd, 1H); 3.55 (dd, 1H); 3.46 (dd, 1H); 3.11 (dd, 1H); 2.15 (s, 3H).

Intermediate 122 (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of 4-chloro-2-methoxyphenol (15.00 g, 0.10 mol) with sodium hydride (4.4 g, 0.11 mol, 60 wt. %) and 3-chloro-2-methylpropene (12.00 g, 0.12 mol) generally according to the procedure described for Intermediate 13 provided 19.3 g (91%) of 4-chloro-2-methoxy-1-[(2-methylprop-2-enyl)oxy]benzene as a colorless oil. Treatment of the allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 afforded 15.5 g (78%) of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol as a pale yellow oil. Treatment of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol (10.00 g, 0.047 mol) with 3-chloroperoxybenzoic acid (20.00 g, 0.089 mol, 77%) followed by potassium carbonate (20.00 g, 0.145 mol) generally according to the Procedure described for Intermediate 9 provided 8.00 g (74%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol as a light yellow oil. Treatment of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (10.8 g, 0.047 mol) with p-toluenesulfonyl chloride (13.5 g, 0.071 mol), diisopropylethylamine (12.15 g, 0.094 mol), and 4-(dimethylamino)pyridine (0.35 g, 2.83 mmol) generally according to the procedure described for Intermediate 45 gave 13.8 g (76%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 113-115° C.; Anal. calcd. for C₁₈H₁₉ClO₅S: C, 56.47; H, 5.00. Found: C, 55.82; H, 4.94.

Intermediate 123 (±)-(5-chloro-7-hydroxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (13.80 g, 0.036 mol) with hydrogen bromide (200 mL, 30 wt. % in acetic acid) generally according to the procedure described for Intermediate 46 afforded 11.7 g (80%) of (±)-(5-chloro-7-hydroxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 135-137° C.; Anal. calcd. for C₁₇H₁₇ClO₅S: C, 55.36; H, 4.65. Found: C, 54.35; H, 4.52.

Intermediate 124 (±)-(5-chloro-2-methyl-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(5-chloro-7-hydroxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (11.7 g, 0.032 mol) with trifluoromethanesulfonic anhydride (10.34 g, 0.037 mol) and diisopropylethylamine (4.74 g, 0.037 mol) generally according to the procedure described for Intermediate 7 provided 13.0 g (82%) of (±)-(5-chloro-2-methyl-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 100-102° C.; Anal. calcd. for C₁₈H₁₆ClF₃O₇S₂: C, 43.16; H, 3.22. Found: C, 43.07; H, 3.04.

Intermediate 125 (−)-benzyl[(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl]carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl (7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (R_(t)=4.39 min, Chiralpak OD, 2-butanol:carbon dioxide 2:8). [α]_(D) ²⁵=−17.46 (c 10.0 in methanol); Anal. calcd. for C₂₂H₂₇NO₄: C, 71.52; H, 7.37; N, 3.79. Found C, 71.2; H, 7.61; N, 3.62.

Intermediate 126 (±)-benzyl[(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl]carbamate

Fraction 2 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl [(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl]carbamate (R_(t)=5.07 min, Chiralpak OD, 2-butanol:carbon dioxide 2:8). [α]_(D) ²⁵=+22.18 (c 10.0 in methanol); Anal. calcd. for C₂₂H₂₇NO₄: C, 71.52; H, 7.37; N, 3.79. Found C, 70.33; H, 7.49; N, 3.5.

Intermediate 127 (±)-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (8.0 g, 20.87 mmol) with [E]-2-tert-butylvinylboronic acid (4.01 g, 31.31 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.82 g, 1.04 mmol), and potassium carbonate (7.21 g, 52.19 mmol) generally according to the procedure described for Intermediate 37 provided 6.54 g (81%) of (±)-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. mp 85-88° C.; Anal. calcd. for C₂₂H₂₆O₄S: C, 68.37; H, 6.78. Found: C, 68.27; H, 6.86.

Intermediate 128 (±)-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (8.0 g, 20.9 mmol) with trans-2-phenylvinylboronic acid (4.63 g, 31.3 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.82 g, 1.04 mmol), and potassium carbonate (7.21 g, 52.2 mmol) generally according to the procedure described for Intermediate 37 provided 6.59 g (78%) of (±)-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a light yellow solid. mp 120-122° C.; Anal. calcd. for C₂₄H₂₂O₄S: C, 70.91; H, 5.45. Found: C, 70.78; H, 5.56.

Intermediate 129 (±)-benzyl {[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.94 g, 7.03 mmol) with diisopropylethylamine (1.36 g, 10.55 mmol) followed by benzyl chloroformate (1.32 g, 7.74 mmol) generally according to the procedure described for Intermediate 12 provided 2.36 g (90%) of (±)-benzyl {[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 134-136° C.; Anal. calcd. for C₂₄H₂₃NO₃: C, 77.19; H, 6.21; N, 3.75. Found: C, 77.08; H, 6.3; N, 3.69.

Intermediate 130 (±)-benzyl({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate

Treatment of (±)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (2.21 g, 6.7 mmol) with diisopropylethylamine (1.3 g, 10.05 mmol) followed by benzyl chloroformate (1.25 g, 7.37 mmol) generally according to the procedure described for Intermediate 12 provided 2.6 g (91%) of (±)-benzyl({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate as a colorless oil. Anal. calcd. for C₂₄H₂₀F₃NO₃: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.5; H, 4.7; N, 3.13. Chiral HPLC separation of (±)-benzyl ({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (Chiralcel OJ, ethanol:hexane 1:1) provided two fractions. Fraction 1 (R_(t)=5.701 min, Chiralcel OJ, ethanol:hexane 1:1); Fraction 2 (R_(t)=7.122 min, Chiralcel OJ, ethanol:hexane 1:1).

Intermediate 131 (−)-benzyl({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl ({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (R_(t)=5.701 min, Chiralcel OJ, ethanol:hexane 1:1). [α]_(D) ²⁵=−61.46 (c 10.0 in methanol); Anal. calcd. for C₂₄H₂₀F₃NO₃: C, 67.44; H, 4.72; N, 3.28. Found C, 67.52; H, 4.67; N, 3.11.

Intermediate 132 (+)-benzyl({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate

Fraction 2 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl ({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (R_(t)=7.122 min, Chiralcel OJ, ethanol:hexane 1:1). [α]_(D) ²⁵=+60.44 (c 10.0 in methanol); Anal. calcd. for C₂₄H₂₀F₃NO₃: C, 67.44; H, 4.72; N, 3.28. Found C, 67.03; H, 4.62; N, 3.2.

Intermediate 133 (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 2,6-dimethylphenylboronic acid (2.35 g, 15.66 mmol), tetrakis(triphenylphosphine)palladium(0) (0.452 g, 0.394 mmol), and barium hydroxide octahydrate (6.17 g, 19.57 mmol) generally according to the procedure described for Intermediate 50 provided 2.27 g (71%) of (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C₂₄H₂₄O₄S: C, 70.56; H, 5.92. Found: C, 69.72; H, 5.87.

Intermediate 134 (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.2 g, 4.14 mmol) with diisopropylethylamine (0.803 g, 6.21 mmol) followed by benzyl chloroformate (0.848 g, 4.97 mmol) generally according to the procedure described for Intermediate 12 provided 1.52 g (95%) of (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. Anal. calcd. for C₂₅H₂₅NO₃: C, 77.49; H, 6.5; N, 3.61. Found: C, 76.66; H, 6.31; N, 3.44. Chiral HPLC separation of (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel OD, ethanol) provided two fractions. Fraction 1 (R_(t)=4.818 min, Chiralcel OD, ethanol); Fraction 2 (R_(t)=6.985 min, Chiralcel OD, ethanol).

Intermediate 135 (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=4.818 min, Chiralcel OD, ethanol). [α]_(D) ²⁵=+60.96 (c 10.0 in methanol); Anal. calcd. for C₂₅H₂₅NO₃: C, 77.49; H, 6.5; N, 3.61. Found: C, 77.11; H, 6.26; N, 3.38.

Intermediate 136 (−)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 2 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=6.985 min, Chiralcel OD, ethanol). [α]_(D) ²⁵=−59.24 (c 10.0 in methanol); Anal. calcd. for C₂₅H₂₅NO₃: C, 77.49; H, 6.5; N, 3.61. Found: C, 76.91; H, 6.37; N, 3.46.

Intermediate 137 (±)-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-thiopheneboronic acid (0.334 g, 2.61 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.389 g (77%) of (±)-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a light yellow solid. mp 90-92° C.; Anal. calcd. for C₂₀H₁₈O₄S₂: C, 62.15; H, 4.69. Found: C, 62.2; H, 4.72.

Intermediate 138 (±)-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (10.0 g, 26.10 mmol) with 2-(trifluoromethyl)phenylboronic acid (7.43 g, 39.12 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (1.02 g, 1.30 mmol), and potassium carbonate (9.01 g, 65.19 mmol) generally according to the procedure described for Intermediate 37 provided 8.46 g (75%) of (±)-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a tan solid. mp 116-118° C.; Anal. calcd. for C₂₃H₁₉F₃O₄S: C, 61.60; H, 4.27. Found: C, 61.91; H, 4.23.

Intermediate 139 (±)-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (3.00 g, 7.83 mmol) with 3-chlorophenylboronic acid (1.84 g, 11.74 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.308 g, 0.391 mmol), and potassium carbonate (2.70 g, 19.57 mmol) generally according to the procedure described for Intermediate 37 provided 2.35 g (72%) of (±)-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a tan solid. mp 100-103° C.; Anal. calcd. for C₂₂H₁₉ClO₄S: C, 63.69; H, 4.62. Found: C, 63.43; H, 4.69.

Intermediate 140 (±)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=9.655 min, Chiralcel OJ, hexane:ethanol 1:1). [α]_(D) ²⁵=+10.48 (c 10.0 in methanol); Anal. calcd. for C₂₃H₂₀ClNO₃: C, 70.14; H, 5.12; N, 3.56. Found C, 69.45; H, 4.92; N, 2.94.

Intermediate 141 (−)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 2 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=16.300 min, Chiralcel OJ, hexane:ethanol 1:1). [α]_(D) ²⁵=−9.64 (c 10.0 in methanol); Anal. calcd. for C₂₃H₂₀ClNO₃: C, 70.14; H, 5.12; N, 3.56. Found C, 69.43; H, 5.06; N, 3.19.

Intermediate 142 (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-methylphenylboronic acid (0.266 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium tert-butoxide (0.366 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.358 g (70%) of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 98-100° C.; Anal. calcd. for C₂₃H₂₂O₄S: C, 70.03; H, 5.62. Found: C, 69.83; H, 5.61.

Intermediate 143 (±)-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.500 g, 1.305 mmol) with 2-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.422 g (81%) of (±)-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. mp 99-101° C.; Anal. calcd. for C₂₂H₁₉FO₄S: C, 66.32; H, 4.81. Found: C, 65.16; H, 4.86.

Intermediate 144 (±)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 13.04 mmol) with 2-methoxyphenylboronic acid (3.96 g, 26.09 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.532 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 3.63 g (68%) of (±)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. mp 151-153° C.; Anal. calcd. for C₂₃H₂₂O₅S: C, 67.3; H, 5.4. Found: C, 66.95; H, 5.43.

Intermediate 145 (±)-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.392 g (75%) of (±)-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid. mp 88-90° C.; Anal. calcd. for C₂₂H₁₉FO₄S: C, 66.32; H, 4.81. Found: C, 65.63; H, 4.84.

Intermediate 146 (±)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (798 g, 6,382.86 mmol) with diisopropylethylamine (0.554 g, 4.29 mmol) followed by benzyl chloroformate (0.536 g, 3.14 mmol) generally according to the procedure described for Intermediate 12 provided 1.01 g (94%) of (±)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. R_(f)=0.41 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C₂₃H₂₀FNO₃: C, 73.2; H, 5.34; N, 3.71. Found: C, 72.96H, 5.38; N, 3.59. Chiral HPLC separation of (±)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak OD, isopropanol:hexane 2:8) provided two fractions. Fraction 1 (R_(t)=7.675 min, Chiralpak OD, isopropanol:hexane 2:8); Fraction 2 (R_(t)=9.182 min, Chiralpak OD, isopropanol:hexane 2:8).

Intermediate 147 (±)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=7.675 min, Chiralpak OD, isopropanol:hexane 2:8). [α]_(D) ²⁵=+41.76 (c 10.0 in methanol); Anal. calcd. for C₂₃H₂₀FNO₃: C, 73.2; H, 5.34; N, 3.71. Found C, 73.01; H, 5.28; N, 3.75.

Intermediate 148 (−)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 2 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=9.182 min, Chiralpak OD, isopropanol:hexane 2:8). [α]_(D) ²⁵=−34.44 (c 10.0 in methanol); Anal. calcd. for C₂₃H₂₀FNO₃: C, 73.2; H, 5.34; N, 3.71. Found C, 73.2; H, 5.39; N, 3.62.

Intermediate 149 (±)-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 13.05 mmol) with 3-methoxyphenylboronic acid (2.97 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 4.48 g (84%) of (±)-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 141-142° C.; Anal. calcd. for C₂₃H₂₂O₅S: C, 67.3; H, 5.4. Found: C, 66.51; H, 5.41.

Intermediate 150 (±)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.4 g, 9.4 mmol) with diisopropylethylamine (1.82 g, 14.10 mmol) followed by benzyl chloroformate (1.92 g, 11.28 mmol) generally according to the procedure described for Intermediate 12 provided 3.28 g (90%) of (±)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. R_(f)=0.51 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C₂₄H₂₃NO₄: C, 74.02; H, 5.95; N, 3.6. Found: C, 73.52; H, 6.06; N, 3.28. Chiral HPLC separation of (±)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak OD, ethanol) provided two fractions. Fraction 1 (R_(t)=6.220 min, Chiralpak OD, ethanol); Fraction 2 (R_(t)=8.373 min, Chiralpak OD ethanol).

Intermediate 151 (+)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=6.220 min, Chiralpak OD, ethanol). [α]_(D) ²⁵=+26.94 (c 10.0 in methanol); Anal. calcd. for C₂₄H₂₃NO₄: C, 74.02; H, 5.95; N, 3.6. Found: C, 73.48; H, 5.98; N, 3.46.

Intermediate 152 (−)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 2 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=8.373 min, Chiralpak OD ethanol). [α]_(D) ²⁵=−26.96 (c 10.0 in methanol); Anal. calcd. for C₂₄H₂₃NO₄: C, 74.02; H, 5.95; N, 3.6. Found: C, 73.52; H, 6.01; N, 3.45.

Intermediate 153 (±)-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.404 g (75%) of (±)-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid. mp 101-103° C.; Anal. calcd. for C₂₂H₁₉ClO₄S: C, 63.69; H, 4.62. Found: C, 63.59; H, 4.52.

Intermediate 154 (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 3-(trifluoromethyl)phenylboronic acid (3.72 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 5.28 g (90%) of (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. mp 90-93° C.; Anal. calcd. for C₂₃H₁₉F₃O₄S: C, 61.6; H, 4.27. Found: C, 61.52; H, 4.21.

Intermediate 155 (±)-benzyl({7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate

Treatment of (±)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (1.67 g, 5.06 mmol) with diisopropylethylamine (0.98 g, 7.59 mmol) followed by benzyl chloroformate (1.04 g, 7.59 mmol) generally according to the procedure described for Intermediate 12 provided 2.1 g (97%) of (±)-benzyl({7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate as a colorless oil. Anal. calcd. for C₂₄H₂₀F₃NO₃: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.08; H, 5.05; N, 3.22. Chiral HPLC separation of (±)-benzyl ({7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (Chiralpak OJ, isopropanol:carbon dioxide 15:85) provided two fractions. Fraction 1 (R_(t)=6.12 min, Chiralpak OJ, isopropanol:carbon dioxide 15:85); Fraction 2 (R_(t)=7.17 min, Chiralpak OJ, isopropanol:carbon dioxide 15:85).

Intermediate 156 (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (11.2 g, 29.22 mmol) with 4-methylphenylboronic acid (5.96 g, 43.84 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (1.15 g, 1.46 mmol), and potassium carbonate (10.10 g, 73.07 mmol) generally according to the procedure described for Intermediate 37 provided 9.8 g (85%) of (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 145-147° C.; Anal. calcd. for C₂₃H₂₂O₄S: C, 70.03; H, 5.62. Found: C, 69.91; H, 5.7.

Intermediate 157 (±)-benzyl {[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (5.8 g, 24.24 mmol) with diisopropylethylamine (4.69 g, 36.35 mmol) followed by benzyl chloroformate (5.17 g, 30.30 mmol) generally according to the procedure described for Intermediate 12 provided 5.05 g (56%) of (±)-benzyl {[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a clear oil. Anal. calcd. for C₂₄H₂₃NO₃: C, 77.19; H, 6.21; N, 3.75. Found: C, 76.97; H, 5.99; N, 3.68. Chiral HPLC separation of (±)-benzyl {[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak OD, methanol:carbon dioxide 1:1) provided two fractions. Fraction 1 (R_(t)=3.735 min, Chiralpak OD, methanol:carbon dioxide 1:1); Fraction 2 (R_(t)=4.381 min, Chiralpak OD, methanol:carbon dioxide 1:1).

Intermediate 158 (±)-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.408 g (78%) of (±)-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid. mp 83-86° C.; Anal. calcd. for C₂₂H₁₉FO₄S: C, 66.32; H, 4.81. Found: C, 66.11; H, 4.61.

Intermediate 159 (±)-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (+)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.367 g (68%) of (±)-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as an orange solid. mp 130-133° C.; Anal. calcd. for C₂₂H₁₉ClO₄S: C, 63.69; H, 4.62. Found: C, 62.82; H, 4.56.

Intermediate 160 (±)-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-(trifluoromethyl)phenylboronic acid (0.372 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.435 g (74%) of (±)-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a light yellow solid. mp 116-118° C.; Anal. calcd. for C₂₃H₁₉F₃O₄S: C, 61.6; H, 4.27. Found: C, 61.37; H, 4.36.

Intermediate 161 (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.61 mmol) with 2,6-dimethylphenylboronic acid (0.783 g, 5.22 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.103 g, 0.131 mmol), and potassium carbonate (0.902 g, 6.52 mmol) generally according to the procedure described for Intermediate 37 provided 0.192 g (18%) of (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C₂₄H₂₄O₄S: C, 70.56; H, 5.92. Found: C, 68.01; H, 5.6.

Intermediate 162 (±)-benzyl {[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.947 g, 3.73 mmol) with diisopropylethylamine (0.725 g, 5.60 mmol) followed by benzyl chloroformate (0.765 g, 4.48 mmol) generally according to the procedure described for Intermediate 12 provided 1.26 g (87%) of (±)-benzyl {[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. Anal. calcd. for C₂₅H₂₅NO₃: C, 77.49; H, 6.5; N, 3.61. Found: C, 77.42; H, 6.57; N, 3.62. Chiral HPLC separation of (±)-benzyl {[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel OJ, methanol:carbon dioxide 4:6) provided two fractions. Fraction 1 (R_(t)=3.12 min, Chiralcel OJ, methanol:carbon dioxide 4:6); Fraction 2 (R_(t)=4.28 min, Chiralcel OJ methanol:carbon dioxide 4:6).

Intermediate 163 2′,6′-difluoro-1,1′-biphenyl-2-ol

Treatment of 2,6-difluorobromobenzene (8.9 g, 46.1 mmol) with 2-methoxybenzeneboronic acid (10.51 g, 69.2 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (1.81 g, 2.3 mmol), and potassium carbonate (15.9 g, 115.3 mmol) generally according to the procedure described for Intermediate 37 provided 4.6 g (45%) of 2′,6′-difluoro-1,1′-biphenyl-2-yl methyl ether. To a solution of 2′,6′-difluoro-1,1′-biphenyl-2-yl methyl ether (4.5 g, 20.4 mmol) in dichloromethane (100 mL) cooled to −78° C. was added boron tribromide (5.11 g, 1.0 M in dichloromethane) and the reaction mixture was allowed to stir for 30 min. The reaction mixture was allowed to warm to room temperature and was quenched by the addition of ice (150 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were washed with water (400 mL), saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, hexanes:ethyl acetate 95:5) provided 3.95 g (94%) of 2′,6′-difluoro-1,1′-biphenyl-2-ol as a colorless oil. Anal. calcd. for C₁₂H₈F₂O: C, 69.9; H, 3.91. Found: C, 68.51; H, 4.06.

Intermediate 164 (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol

Treatment of 2′,6′-difluoro-1,1′-biphenyl-2-ol (3.8 g, 18.43 mmol) with potassium carbonate (10.19 g, 73.72 mmol) and allyl bromide (2.67 g, 22.11 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-2′,6′-difluoro-1,1′-biphenyl-2-ol. Treatment of the 3-allyl-2′,6′-difluoro-1,1′-biphenyl-2-ol (3.41 g, 13.85 mmol) with 3-chloroperoxybenzoic acid (7.25 g, 41.54 mmol, 77%) followed by potassium carbonate (4.78 g, 34.62 mmol) generally according to the procedure described for Intermediate 9 afforded 3.5 g (72%) of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol as an amber oil. Anal. calcd. for C₁₅H₁₂F₂O₂: C, 68.7; H, 4.61. Found C, 67.26; H, 4.5.

Intermediate 165 (±)-benzyl {[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-1-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.54 g, 5.17 mmol) with diisopropylethylamine (1.02 g, 7.76 mmol) and benzyl chloroformate (0.971 g, 5.69 mmol) generally according to the procedure described for Intermediate 12 gave 2.02 g (98%) of (±)-benzyl {[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. Anal. calcd. for C₂₃H₁₉F₂NO₃: C, 69.87; H, 4.84; N, 3.54. Found C, 69.54; H, 4.87; N, 3.31.

Intermediate 166 2′,6′-dichloro-1,1′-biphenyl-2-ol

Treatment of 2,6-dichlorobromobenzene (25.0 g, 0.110 mol) with 2-methoxybenzeneboronic acid (25.22 g, 0.166 mol), dichlorobis(tri-o-tolylphosphine)palladium(II) (2.33 g, 2.96 mmol), and potassium carbonate (34.15 g, 0.247 mmol) generally according to the procedure described for Intermediate 37 provided 21.5 g (77%) of 2′,6′-dichloro-1,1′-biphenyl-2-yl methyl ether. Treatment of 2′,6′-dichloro-1,1′-biphenyl-2-yl methyl ether (19.0 g, 75.06 mmol) with boron tribromide (18.78 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided 17.89 g (99%) of 2′,6′-dichloro-1,1′-biphenyl-2-ol as a light yellow solid. mp 100-103° C.; Anal. calcd. for C₁₂H₈Cl₂O: C, 60.28H, 3.37. Found: C, 60.29; H, 3.13.

Intermediate 167 (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of 2′,6′-dichloro-1,1′-biphenyl-2-ol (17.95 g, 75.06 mmol) with potassium carbonate (41.38 g, 299.43 mmol) and allyl bromide (10.89 g, 90.08 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-2′,6′-dichloro-1,1′-biphenyl-2-ol. Treatment of 3-allyl-2′,6′-dichloro-1,1′-biphenyl-2-ol (16.5 g, 59.10 mmol) with 3-chloroperoxybenzoic acid (30.59 g, 177.3 mmol, 77%) followed by potassium carbonate (20.41 g, 14.77 mmol) generally according to the procedure described for Intermediate 9 afforded 11.2 g (64%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (11.2 g, 37.94 mmol) with p-toluenesulfonyl chloride (8.68 g, 45.53 mol) generally according to the procedure described for Intermediate 10 gave 15.2 g (89%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C₂₂H₁₈Cl₂O₄S: C, 58.8; H, 4.04. Found: C, 58.1; H, 4.05.

Intermediate 168 (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.290 g, 0.877 mmol) with diisopropylethylamine (0.170 g, 1.315 mmol) followed by benzyl chloroformate (0.165 g, 0.965 mmol) generally according to the procedure described for Intermediate 12 provided 0.352 g (94%) of (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 198-200° C.; Anal. calcd. for C₂₃H₁₉Cl₂NO₃: C, 64.5; H, 4.47; N, 3.27. Found: C, 64.2; H, 4.43; N, 3.21. Chiral HPLC separation of (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (R_(t)=5.174 min, Chiralcel AD, ethanol:hexane 1:1); Fraction 2 (R_(t)=6.229 min, Chiralcel AD, ethanol:hexane 1:1).

Intermediate 169 (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2,4-dichlorophenylboronic acid (3.73 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 4.5 g (75%) of (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C₂₂H₁₈Cl₂O₄S: C, 58.8; H, 4.04. Found: C, 59.01; H, 4.09.

Intermediate 170 (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.9 g, 5.75 mmol) with diisopropylethylamine (1.11 g, 8.62 mmol) followed by benzyl chloroformate (1.18 g, 6.89 mmol) generally according to the procedure described for Intermediate 12 gave 2.14 g (87%) of (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 87-89° C.; Anal. calcd. for C₂₃H₁₉Cl₂NO₃: C, 64.5; H, 4.47; N, 3.27. Found: C, 64.65; H, 4.78; N, 3.08. Chiral HPLC separation of (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel AD, methanol:water 95:5) provided two fractions. Fraction 1 (R_(t)=8.094 min, Chiralcel AD, methanol:water 95:5); Fraction 2 (R_(t)=9.152 min, Chiralcel AD methanol:water 95:5).

Intermediate 171 (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=8.094 min, Chiralcel AD, methanol:water 95:5). [α]_(D) ²⁵=+14.36 (c 10.0 in methanol); Anal. calcd. for C₂₃H₁₉Cl₂NO₃: C, 64.5; H, 4.47; N, 3.27. Found: C, 64.71; H, 4.76; N, 3.34.

Intermediate 172 (−)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 2 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=9.152 min, Chiralcel AD methanol:water 95:5). [α]_(D) ²⁵=−14.66 (c 10.0 in methanol); Anal. calcd. for C₂₃H₁₉Cl₂NO₃: C, 64.5; H, 4.47; N, 3.27. Found: C, 63.95; H, 4.68; N, 3.27.

Intermediate 173 (±)-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2,4-dimethoxyphenylboronic acid (3.56 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 3.3 g (57%) of (±)-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid. mp 120-123° C.; Anal. calcd. for C₂₄H₂₄O₆S: C, 65.44; H, 5.49. Found: C, 64.99; H, 5.46.

Intermediate 174 (±)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.42 g, 4.41 mmol) with diisopropylethylamine (0.855 g, 6.62 mmol) followed by benzyl chloroformate (0.828 g, 4.85 mmol) generally according to the procedure described for Intermediate 12 provided 1.58 g (85%) of (±)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. Anal. calcd. for C₂₅H₂₅NO₅: C, 71.58; H, 6.01; N, 3.34. Found: C, 71.24; H, 5.92; N, 3.09. Chiral HPLC separation of (±)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel OD, ethanol) provided two fractions. Fraction 1 (R_(t)=5.107 min, Chiralcel OD, ethanol); Fraction 2 (R_(t)=6.134 min, Chiralcel OD, ethanol).

Intermediate 175 (+)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=5.107 min, Chiralcel OD, ethanol). [α]_(D) ²⁵=+21.96 (c 10.0 in methanol); Anal. calcd. for C₂₅H₂₅NO₅: C, 71.58; H, 6.01; N, 3.34. Found: C, 70.12; H, 6.11; N, 3.12.

Intermediate 176 (−)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 2 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=6.134 min, Chiralcel OD, ethanol). [α]_(D) ²⁵=−23.20 (c 10.0 in methanol); Anal. calcd. for C₂₅H₂₅NO₅: C, 71.58; H, 6.01; N, 3.34. Found: C, 70.22; H, 6.1; N, 3.28.

Intermediate 177 (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2,4-difluorophenylboronic acid (3.09 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.651 mmol), and potassium carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 afforded 4.43 g (82%) of (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 116-118° C.; Anal. calcd. for C₂₂H₁₈F₂O₄S: C, 63.45; H, 4.36. Found: C, 63.3; H, 4.11.

Intermediate 178 (±)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.0 g, 6.72 mmol) with diisopropylethylamine (1.30 g, 10.07 mmol) followed by benzyl chloroformate (1.26 g, 7.37 mmol) generally according to the procedure described for Intermediate 12 gave 2.14 g (81%) of (±)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 78-80° C.; Anal. calcd. for C₂₃H₁₉F₂NO₃: C, 69.87; H, 4.84; N, 3.54. Found: C, 69.76; H, 4.8; N, 3.35. Chiral HPLC separation of (±)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (R_(t)=9.117 min, Chiralpak AD, ethanol:hexane 1:1); Fraction 2 (R_(t)=9.424 min, Chiralpak AD ethanol:hexane 1:1).

Intermediate 179 (+)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (+)benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=9.117 min, Chiralpak AD, ethanol:hexane 1:1). [α]_(D) ²⁵=+13.0 (c 10.0 in methanol); Anal. calcd. for C₂₃H₁₉F₂NO₃: C, 69.87; H, 4.84; N, 3.54. Found: C, 69.28; H, 5.23; N, 3.47.

Intermediate 180 (−)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 2 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=9.424 min, Chiralpak AD ethanol:hexane 1:1). [α]_(D) ²⁵=−13.68 (c 10.0 in methanol); Anal. calcd. for C₂₃H₁₉F₂NO₃: C, 69.87; H, 4.84; N, 3.54. Found: C, 69.65; H, 5.06; N, 3.57.

Intermediate 181 4′-chloro-2′-methyl-1,1′-biphenyl-2-ol

Treatment of 2-bromo-5-chlorotoluene (5.0 g, 24.33 mmol) with 2-methoxybenzeneboronic acid (4.8 g, 31.63 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.478 g, 0.608 mmol), and potassium carbonate (8.41 g, 60.83 mmol) generally according to the procedure described for Intermediate 37 provided 5.05 g (89%) of 4′-chloro-2′-methyl-1,1′-biphenyl-2-yl methyl ether. Treatment of 4′-chloro-2′-methyl-1,1′-biphenyl-2-yl methyl ether (5.05 g, 21.48 mmol) with boron tribromide (5.37 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided 4.58 g (97%) of 4′-chloro-2′-methyl-1,1′-biphenyl-2-ol as a yellow oil. Anal. calcd. for C₁₃H₁₁ClO: C, 71.4; H, 5.07. Found: C, 71.03; H, 4.84.

Intermediate 182 (±)-[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol

Treatment of 4′-chloro-2′-methyl-1,1′-biphenyl-2-ol (4.54 g, 20.78 mmol) with potassium carbonate (11.47 g, 83.04 mmol) and allyl bromide (3.01 g, 24.91 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-4′-chloro-2′-methyl-1,1′-biphenyl-2-ol. Treatment of 3-allyl-4′-chloro-2′-methyl-1,1′-biphenyl-2-ol (4.5 g, 17.39 mmol) with 3-chloroperoxybenzoic acid (12.0 g, 69.57 mmol, 77%) followed by potassium carbonate (6.0 g, 43.48 mmol) generally according to the procedure described for Intermediate 9 afforded 2.9 g (61%) of (±)-[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol as a colorless oil. Anal. calcd. for C₁₆H₁₅ClO₂: C, 69.95; H, 5.5. Found: C, 69.23; H, 5.42.

Intermediate 183 (±)-[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (2.78 g, 10.11 mmol) with p-toluenesulfonyl chloride (2.31 g, 12.14 mol) generally according to the procedure described for Intermediate 10 gave 4.04 g (93%) of (±)-[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C₂₃H₂₁ClO₄S: C, 64.4; H, 4.93. Found: C, 64.24; H, 4.93.

Intermediate 184 No Compound Intermediate 185 (+)-[7-bromo-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Fraction 1 obtained as a white solid from the chiral HPLC separation of 7-bromo-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (R_(t)=6.220 min, Chiraicel AD, ethanol). [α]_(D) ²⁵=+23.4 (c 10.0 in methanol); mp 96-99° C.

Intermediate 186 (−)-[7-bromo-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Fraction 2 obtained as a white solid from the chiral HPLC separation of 7-bromo-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (R_(t)=6.220 min, Chiraicel AD, ethanol). [α]_(D) ²⁵=−22.00 (c 10.0 in methanol); mp 96-99° C.

Intermediate 187 (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,3-dimethylphenyl)boronic acid (0.294 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.335 g (62%) of (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:4).

Intermediate 188 (±)-[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.783 mmol) with (2,3-dimethoxylphenyl)boronic acid (0.427 g, 2.35 mmol) generally according to the procedure described for Intermediate 184 provided 0.283 g (82%) of (±)-[7-(2,3-dimethoxylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:4).

Intermediate 189 (±)-[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,3-difluorophenyl)boronic acid (0.618 g, 3.91 mmol) generally according to the procedure described for Intermediate 184 provided 0.090 g (77%) of (±)-[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:4).

Intermediate 190 (±)-[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,5-dimethylphenyl)boronic acid (0.294 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.430 g (81%) of (±)-[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:4).

Intermediate 191 (±)-[7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,5-difluorophenyl)boronic acid (0.309 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.360 g (66%) of (±)-[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:4).

Intermediate 192 [7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.43 g, 3.73 mmol) with (2,5-dichlorophenyl)boronic acid (1.07 g, 5.59 mmol) generally according to the procedure described for Intermediate 184 provided 1.49 g (88%) of (±)[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:4.

Intermediate 193 (±)-[7-(2,5-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,5-dimethoxyphenyl)boronic acid (0.356 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.291 g (51%) of (±)-[7-(2,5-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:4).

Intermediate 194 (±)-[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (5-chloro-2-methylphenyl)boronic acid (0.334 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.451 g (81%) of (+)-[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:4).

Intermediate 195 (±)-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (5-chloro-2-methoxyphenyl)boronic acid (0.365 g, 1.96 mmol generally according to the procedure described for Intermediate 184 provided 0.382 g (66%) of (±)-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:4).

Intermediate 196 (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of 2,4,6-trichlorobromobenzene (14.5 g, 55.69 mmol) with 2-methoxybenzeneboronic acid (12.69 g, 83.54 mol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.656 g, 0.835 mmol), and potassium carbonate (19.21 g, 139.22 mmol) generally according to the procedure described for Intermediate 37 provided 9.8 g (61%) of 2′,4′,6′-trichloro-1,1′-biphenyl-2-yl methyl ether. To a solution of 2′,4′,6′-trichloro-1,1′-biphenyl-2-yl methyl ether (9.8 g, 34.08 mmol) in dichloromethane (100 mL) cooled to −78° C. was added boron tribromide (9.38 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided 9.2 g of a yellow solid. Treatment of 2′,4′,6′-trichloro-1,1′-biphenyl-2-ol (9.17 g, 33.52 mmol) with potassium carbonate (18.53 g, 134.1 mmol) and allyl bromide (4.46 g, 36.87 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-2′,4′,6′-trichloro-1,1′-biphenyl-2-ol. Treatment of 3-allyl-2′,4′,6′-trichloro-1,1′-biphenyl-2-ol. (10.35 g, 33.00 mmol) with 3-chloroperoxybenzoic acid (17.08 g, 99.00 mmol, 77%) followed by potassium carbonate (11.40 g, 82.51 mmol) generally according to the procedure described for Intermediate 9 afforded 10.4 g (95%) of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (10.38 g, 31.49 mmol) with p-toluenesulfonyl chloride (7.20 g, 37.79 mol) generally according to the procedure described for Intermediate 10 gave 10.5 g (68%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 178-180° C.

Intermediate 197 (±)-(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.0 g, 10.44 mmol) with pyridin-3-ylboronic acid (3.85 g, 31.31 mmol), tetrakis tri-phenylphosphine palladium (0.362 g, 0.052 mmol), and potassium carbonate (3.61 g, 26.09 mmol) generally according to the procedure described for Intermediate 184 provided 2.47 g (62%) of (±)-(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonates a light yellow solid. R_(f)=0.43 (silica, ethyl acetate:hexanes 1:4).

Intermediate 198 (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methanol

To a solution of 2-nitrophenol (13.9 g, 100 mmol) in N,N-dimethylformamide (300 mL) was added with sodium hydride (4.2 g, 100 mmol 60%) followed by allyl bromide (13.3 g, 110 mmol) and the reaction was allowed to stir at room temperature for 2 hours The reaction mixture was diluted with water (500 mL) to dissolve any solids and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give 1-(allyloxy)-2-nitrobenzene. The oil was re-dissolved in mesitylene (500 mL) and heated at reflux for 3 d. Removal of the solvent in vacuo provided a crude oil. Purification by flash column chromatography (silica, dichloromethane:hexanes 0.5:9.5) provided 6.8 g, (50%) of 2-allyl-6-nitrophenol as a yellow oil. To a solution of 2-allyl-6-nitrophenol (6.6 g, 36.84 mmol) in dichloromethane (300 mL) was added 3-chloroperoxybenzoic acid (77%, 16.5 g, 73.67 mmol) The reaction mixture was allowed to stir at room temperature for 8 h. The reaction mixture was washed with a 1:1 solution of 10% sodium sulfite:saturated sodium bicarbonate (2×300 mL). The solvent was removed in vacuo to give crude yellow oil. The oil was diluted with methanol (300 mL) and added to a solution of potassium carbonate (15.0 g, 108.5 mmol) the solution was allowed to stir at room temperature 2 h. The solvent was removed in vacuo. The residue was washed with water (1000 mL) and ethyl acetate (500 mL). The aqueous layer was acidified with 1 N aqueous hydrogen chloride and washed with ethyl acetate (500 mL). The combined organics were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate) and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, dichloromethane:hexanes 4:10) provided 3.18 g (44%) of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methanol as yellow solid. mp 63-65° C.

Intermediate 199 (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methanol (3.14 g, 16.09 mol) in dichloromethane (100 mL) was added diisopropylethyl amine (4.16 g, 32.18 mmol), N,N-dimethylaminopyridine (0.39 g, 3.2 mmol), and p-toluenesulfonyl chloride (4.6 g, 24.13 mmol) the reaction was allowed to stir at room temperature for 12 h. The reaction was diluted with dichloromethane (500 mL), washed with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, dichloromethane:hexanes 3:10) afforded 5.2 g (94%) of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as off-white solid. mp 129-131° C.

Intermediate 200 (±)-(7-amino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate

A solution of (±)-(7-amino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.8 g, 13.74 mmol) in ethanol (400 mL) and palladium on carbon (1.4 g, 5 wt. %) was shaken under an H₂ atmosphere (50 psi) for 12 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo provided 4.4 g (99%) of (±)-(7-amino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a light brown oil.

Intermediate 201 (±)-{7-[(4-methylphenyl)amino]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) in toluene (20 mL) with 1-bromo-4-methylbenzene (0.513 g, 30 mmol) dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (0.061 g, 0.075 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.125 g, 0.225 mmol), sodium tert-butoxide (0.18 g, 1.875 mmol) the reaction was allowed to reflux 3 h. The solvent was removed in vacuo. The residue was washed with water (100 mL) and ethyl acetate (50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:10) afforded 0.36 g (29%) of (±)-{7-[(4-methylphenyl)amino]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow solid. mp 118-120° C.

Intermediate 202 (±)-{7-[(4-chlorophenyl)amino]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-amino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) with 1-bromo-4-chlorobenzene (0.570 g, 3.0 mmol) generally according to the procedure described for Intermediate 37 provided 0.77 g (57%) of (+)-{7-[(4-chlorophenyl)amino]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. mp 132-134° C.

Intermediate 203 (±)-{7-[(3,4-dimethylphenyl)amino]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate

Treatment of (±)-(7-amino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) with 4-bromo-1,2-dimethylbenzene (0.558 g, 3.0 mmol), generally according to the procedure described for Intermediate 202 provided 0.51 g (38%) (±)-{7-[(3,4-dimethylphenyl)amino]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow solid. mp 88-90° C.

Intermediate 204

(±)-benzyl {[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-benzyl[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.7 g, 8.39 mmol) with diisopropylethylamine (1.63 g, 12.59 mmol) and benzyl chloroformate (1.72 g, 10.07 mmol) generally according to the procedure described for Intermediate 12 provided 3.21 g (91%) of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.

Intermediate 205 (±)-benzyl {[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-benzyl[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.979 g, 3.15 mmol) with diisopropylethylamine (0.612 g, 4.73 mmol) and benzyl chloroformate (0.646 g, 3.79 mmol) generally according to the procedure described for Intermediate 12 provided 1.2 g (96%) of (+)-benzyl[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]carbamate as a colorless oil.

Intermediate 206 (+)-benzyl {[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]carbamate (R_(t)=7.725 min, Chiralcel AD, ethanol:hexane 1:1). [α]_(D) ²⁵=+12.8 (c 10.0 in methanol).

Intermediate 207 (−)-benzyl {[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 2 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]carbamate (R_(t)=9.542 min, Chiralcel AD, ethanol:hexane 1:1). [α]_(D) ²⁵=−4.8 (c 10.0 in methanol).

Intermediate 208 (+)-benzyl {[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]carbamate (R_(t)=4.340 min, Chiralcel AD, isopropanol:hexane 2:8). [α]_(D) ²⁵=+18.8 (c 10.0 in methanol).

Intermediate 209 (−)-benzyl {[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 2 obtained as a colorless oil from the chiral HPLC separation of (+)benzyl[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]carbamate (R_(t)=5.251 min, Chiralcel AD, isopropanol:hexane 2:8). [α]_(D) ²⁵=−16.8 (c 10.0 in methanol).

Intermediate 210 (±)-benzyl {[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-benzyl[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (3.1 g, 11.32 mmol) with diisopropylethylamine (2.19 g, 16.98 mmol) and benzyl chloroformate (2.37 g, 12.45 mmol) generally according to the procedure described for Intermediate 12 provided 4.12 g (89%) of (±)-benzyl {[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.

Intermediate 211 (±)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-benzyl[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.83 g, 8.61 mmol) with diisopropylethylamine (1.67 g, 12.92 mmol) and benzyl chloroformate (1.76 g, 10.33 mmol) generally according to the procedure described for Intermediate 12 provided 3.46 g (87%) of (±)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.

Intermediate 212 (±)-benzyl[(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]carbamate

Treatment of (±)-1-(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine (0.770 g, 3.40 mmol) with diisopropylethylamine (0.660 g, 5.1 mmol) and benzyl chloroformate (0.778 g, 4.08 mmol) generally according to the procedure described for Intermediate 12 provided 0.702 g (57%) of (±)-benzyl[(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]carbamate as an amber oil.

Intermediate 213 (±)-benzyl{[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate

Treatment of (±)-[(N-methyl-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.932 g, 3.4 mmol) with diisopropylethylamine (0.66 g, 5.11 mmol) and benzyl chloroformate (0.778 g, 4.08 mmol) generally according to the procedure described for Intermediate 12 provided 1.25 g (86%) of (±)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate as a colorless oil.

Intermediate 214 (+)-benzyl{[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate

Treatment of (±)-[(N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.67 g, 32.64 mmol) with diisopropylethylamine (0.512 g, 3.97 mmol) and benzyl chloroformate (0.605 g, 3.17 mmol) generally according to the procedure described for Intermediate 12 provided 0.790 g (77%) of (±)-benzyl {[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate as a colorless oil.

Intermediate 215 (±)-benzyl{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate

Treatment of (±)-[(N-methyl-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.1 g, 3.57 mmol) with diisopropylethylamine (0.69 g, 5.35 mmol) and benzyl chloroformate (0.0.82 g, 4.28 mmol) generally according to the procedure described for Intermediate 12 provided 1.6 g (99%) of (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate as a colorless oil.

Intermediate 216 (±)-benzyl{[7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate

Treatment of (±)-(7-bromo-2,3-dihydro-benzofuran-2-ylmethyl)carbamate (0.80 g, 2.21 mmol) with pyridine-3-boronic acid (0.407 g, 3.31 mmol) generally according to the procedure described for Intermediate 37 provided 0.213 g (27%) of (±)-benzyl {[7-pyridine-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate as a colorless oil.

Intermediate 217 (±)-benzyl{[7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-(7-bromo-2,3-dihydro-benzofuran-2-ylmethyl)carbamate (1.3 g, 3.59 mmol) with 2,3-dichlorophenylboronic acid (1.03 g, 5.38 mmol) generally according to the procedure described for Intermediate 37 provided 0.93 g (63%) of (±)-benzyl{[7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a yellow oil.

Intermediate 218 (±)-benzyl{[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-(7-bromo-2,3-dihydro-benzofuran-2-ylmethyl)carbamate (3.2 g, 8.83 mmol) with 2,5-dichlorophenylboronic acid (2.54 g, 13.24 mmol) generally according to the procedure described for Intermediate 37 provided 0.299 g (27%) of (±)-benzyl {[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a yellow oil.

Intermediate 219 (±)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-{[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine (1.1 g, 3.57 mmol) with diisopropylethylamine (0.69 g, 5.35 mmol) and benzyl chloroformate (0.0.82 g, 4.28 mmol) generally according to the procedure described for Intermediate 12 provided 1.6 g (99%) of (±)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.

Intermediate 220 (±)-benzyl methyl{[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Treatment of (±)-N-methyl-1-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.1 g, 3.57 mmol) with diisopropylethylamine (0.69 g, 5.35 mmol) and benzyl chloroformate (0.0.82 g, 4.28 mmol) generally according to the procedure described for Intermediate 12 provided 1.6 g (99%) of (±)-benzyl methyl{[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.

Intermediate 221 (+)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate. [α]_(D) ²⁵=+7.8 (c 10.0 in methanol).

Intermediate 222 (−)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate

Fraction 1 obtained as a colorless oil from the chiral HPLC separation of (±)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate. [α]_(D) ²⁵=−6.2 (c 10.0 in methanol).

Intermediate 223 (±)-[7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (±)-[7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (3.59 g, 12.1 mmol) with p-toluenesulfonyl chloride (3.6 g, 18.2 mmol) generally according to described for Intermediate 10 provided 3.82 g (70%) (±)-[7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. mp 95-97° C.

Intermediate 224 (−)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate

Treatment of (−)-[7-bromo-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.0 g, 5.22 mmol) with 2-methylphenylboronic acid (1.06 g, 7.83 mmol) generally according to described for Intermediate 37 provided 1.71 g (83%) (−)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. [α]_(D) ²⁵=−44.6 (c 10.0 in methanol).

Intermediate 225 (S)-1-Benzyloxy-3-(5-fluoro-2-methoxy-phenyl)propan-2-ol

To a solution of 4-fluoro-2-bromanisole (12.6 ml, 0.1 mol) in anhydrous tetrahydrofuran at −78° C. was added n-butyllithium (39 ml, 2.5 M in hexane) and the resulting mixture was allowed to stir at −78° C. for 3 h. Copper(I) bromide-dimethylsulfide (10.0 g, 0.05 mol) was then added at −78° C. and the reaction mixture was allowed to warm to −40° C. over 2 h. Benzyl(S)-(+)-glycidyl ether (3.71 ml, 0.025 mol) was added at −60° C. followed by boron trifluoride diethyl etherate (0.15 ml, 1.2 mmol) and the reaction mixture was allowed to warm to room temperature over 12 h. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) afforded 5.0 g (70%) of (S)-1-benzyloxy-3-(5-fluoro-2-methoxy-phenyl)propan-2-ol as a colorless oil. HRMS ESI m/e 308.1666 [M+NH4]⁺, Calc'd m/e 308.1662 [M+NH4]⁺; [α]_(D) ²⁵=+8.1 (c 0.89% in methanol).

Intermediate 226 (S)-1-Benzyloxy-3-(5-chloro-2-methoxy-phenyl)propan-2-ol

Treatment of 4-chloro-2-bromanisole (21.5 g, 0.1 mol) generally according to the procedure described for Intermediate 225 provided 5.1 g (67%) of (S)-1-benzyloxy-3-(5-chloro-2-methoxy-phenyl)propan-2-ol as a colorless oil. HRMS ESI m/le 307.1096 [M+H]⁺, Calc'd 307.1101; [α]_(D) ²⁵=+6.6 (c 1% in methanol).

Intermediate 227 (S)-1-Benzyloxy-3-(2-methoxy-5-methyl-phenyl)propan-2-ol

Treatment of 2-bromo-4-methylanisole (14.05 ml, 0.1 mol) generally according to the procedure described for Intermediate 225 afforded 6.74 g (96%) of (S)-1-benzyloxy-3-(2-methoxy-5-methyl-phenyl)propan-2-ol as a colorless oil. HRMS EI n/e 286.1565 (M)⁺, Calc'd. 286.1569; [α]_(D) ²⁵=+15.67 (c 9.57 in methanol).

Intermediate 228 (S)-1-Benzyloxy-3-(2-methoxy-phenyl)propan-2-ol

Treatment of 2-bromoanisole (12.1 ml, 0.1 mol) generally according to the procedure described for Intermediate 225 gave 5.4 g (82%) of (S)-1-benzyloxy-3-(2-methoxyphenyl)propan-2-ol as a colorless oil. HRMS EI m/e 272.1413 (M)⁺, Calc'd. 272.1412. [α]_(D) ²⁵=+18.07 (c 7.86 in methanol).

Intermediate 229 (S)-1-Benzyloxy-3-(2′,6′-dichlor-5-fluoro-2-methoxybiphenyl-3-yl)propan-2-ol

To a solution of 3-bromo-2′,6′-dichloro-5-fluoro-2-methoxy-biphenyl (2.2 g, 6.3 mmol) in anhydrous tetrahydrofuran at 0° C. was added isopropylmagnesium chloride (3.45 ml, 2.0 M in hexane) and the resulting mixture was allowed to stir at 0° C. for 4 h. The reaction mixture was cooled to −30° C. and copper(I) cyanide (0.28 g, 3.1 mmol) in tetrahydrofuran was added and the reaction mixture was allowed to stir at −30° C. for 1 h. Benzyl(S)-(+)-glycidyl ether (0.48 ml, 3.1 mmol) was then added at −30° C. and the reaction mixture was allowed to warm to room temperature for 12 h. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 1.28 g (94%) of (S)-1-benzyloxy-3-(2′,6′-dichlor-5-fluoro-2-methoxybiphenyl-3-yl)propan-2-ol as a colorless oil. HRMS ESI m/e 435.0946 [M−H]⁻, Calc'd 435.0930; [α]_(D) ²⁵=+2.8 (c 8.14 in dimethylsulfoxide).

Intermediate 230 (1S)-2-bromo-1-(5-fluoro-2-hydroxybenzyl)ethyl acetate

A solution of (S)-1-benzyloxy-3-(5-fluoro-2-methoxy-phenyl)propan-2-ol (5.17 g, 17.8 mmol) in hydrogen bromide (40 ml, 30 wt. % in acetic acid) was heated to 70° C. and allowed to stir for 12 h. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed with ammonium hydroxide. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) afforded 3.60 g (70%) of (1S)-2-bromo-1-(5-fluoro-2-hydroxybenzyl)ethyl acetate as a light brown oil. Elemental Analysis for: C₁₁H₁₂BrFO₃ Theory: C, 45.38H, 4.15 Found: C, 45.24H, 4.09.

Intermediate 231 (1S)-2-bromo-1-(5-chloro-2-hydroxybenzyl)ethyl acetate

Treatment of (S)-1-benzyloxy-3-(5-chloro-2-methoxy-phenyl)propan-2-ol (5.4 g, 17.6 mmol) generally according to the procedure described for Intermediate 230 gave 3.8 g (70%) of (1S)-2-bromo-1-(5-chloro-2-hydroxybenzyl)ethyl acetate as a light brown oil. HRMS EI m/e 305.9647 (M)⁺.

Intermediate 232 (1S)-2-bromo-1-(2-hydroxy-5-methylbenzyl)ethyl acetate

Treatment of (S)-1-benzyloxy-3-(2-methoxy-5-methyl-phenyl)propan-2-ol (6.7 g, 23.3 mmol) generally according to the procedure described for Intermediate 230 provided 6.24 g (93%) of (1S)-2-bromo-1-(2-hydroxy-5-methylbenzyl)ethyl acetate as a yellow oil. MS EI m/e 286 (M)⁺; [α]_(D) ²⁵=−2.41 (c 8.29 in methanol).

Intermediate 233 (1S)-2-bromo-1-(2-hydroxybenzyl)ethyl acetate

Treatment of (S)-1-benzyloxy-3-(2-methoxy-phenyl)propan-2-ol (5.40 g, 19.8 mmol) generally according to the procedure described for Intermediate 230 provided 3.42 g (63%) of (1S)-2-bromo-1-(2-hydroxybenzyl)ethyl acetate as a yellow oil. [α]_(D) ²⁵=−12.2 (c 1% in methanol). Elemental Analysis for: C₁₆H₁₅BrO₃ Theory: C, 48.37H, 4.80 Found: C, 48.48H, 4.78.

Intermediate 234 3-[(2S)-2-(acetyloxy)-3-bromopropyl]-2′,6′-dichloro-5-fluorobiphenyl-2-yl acetate

Treatment of (S)-1-benzyloxy-3-(2′,6′-dichlor-5-fluoro-2-methoxybiphenyl-3-yl)propan-2-ol (1.28 g, 2.9 mmol) generally according to the procedure described for Intermediate 230 provided 1.12 g (80%) of 3-[(2S)-2-(acetyloxy)-3-bromopropyl]-2′,6′-dichloro-5-fluorobiphenyl-2-yl acetate as a light yellow oil. HRMS ESI m/e 476.9686 [M+H]⁺, Calc'd. 476.9671; [α]_(D) ²⁵=+13.2 (c 1% in methanol).

Intermediate 235 (S)-2-(3-Bromo-2-hydroxy-propyl)-4-fluoro-phenol

To a solution of (1S)-2-bromo-1-(5-fluoro-2-hydroxybenzyl)ethyl acetate (3.57 g, 12.2 mmol) in methanol was added hydrogen chloride (1.0 M in diethylether, 49 ml) and the reaction mixture was allowed to stir at room temperature for 12 h. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) afforded 2.95 g (97%) of (S)-2-(3-bromo-2-hydroxy-propyl)-4-fluoro-phenol as a colorless oil. HRMS ESI nm/e 246.9761 [M−H]⁺; Calc'd 246.9755. [α]_(D) ²⁵=+8.2° (c 0.71% in methanol).

Intermediate 236 (S)-2-(3-Bromo-2-hydroxy-propyl)-4-chloro-phenol

Treatment of (1S)-2-bromo-1-(5-chloro-2-hydroxybenzyl)ethyl acetate (2.47 g, 3.2 mmol) generally according to the procedure described for Intermediate 235 gave 1.68 g (79%) of (S)-2-(3-bromo-2-hydroxy-propyl)-4-chloro-phenol as a yellow oil. [α]_(D) ²⁵=+9.8° (c 1% in methanol), HRMS EI m/e 263.956 (M)⁺.

Intermediate 237 (S)-2-(3-Bromo-2-hydroxy-propyl)-4-methyl-phenol

Treatment of (1S)-2-bromo-1-(2-hydroxy-5-methylbenzyl)ethyl acetate (6.24 g, 22 mmol) generally according to the procedure described for Intermediate 235 afforded 5.0 g (94%) of (S)-2-(3-bromo-2-hydroxy-propyl)-4-methyl-phenol as a colorless oil. [α]_(D) ²⁵=+13.8 (c 1% in methanol), HRMS ESI m/e 243.0020 [M−H]⁻, Calc'd. 243.0021.

Intermediate 238 (S)-2-(3-Bromo-2-hydroxy-propyl)-phenol

Treatment of (1S)-2-bromo-1-(2-hydroxybenzyl)ethyl acetate (3.42 g, 12.5 mmol) generally according to the procedure described for Intermediate 235 provided 2.71 g (93%) of (S)-2-(3-bromo-2-hydroxy-propyl)-phenol as a light yellow oil. MS ES m/e 229.0 [M−H]⁻; [α]_(D) ²⁵=+16.46 (c 8.14 in methanol).

Intermediate 239 (S)-3-(3-Bromo-2-hydroxy-propyl)-2′,6′-dichloro-5-fluoro-biphenyl-2-ol

Treatment of 3-[(2S)-2-(acetyloxy)-3-bromopropyl]-2′,6′-dichloro-5-fluorobiphenyl-2-yl acetate (1.6 g, 33.4 mmol) generally according to the procedure described for Intermediate 235 gave 1.48 g (99%) of (S)-3-(3-bromo-2-hydroxy-propyl)-2′,6′-dichloro-5-fluoro-biphenyl-2-ol as a light yellow oil. HRMS EI m/e 391.9391 (M)⁺, Calc'd. 391.9391; [α]_(D) ²⁵=−4.76 (c 7.14 in methanol).

Intermediate 240 (R)-2-Bromomethyl-5-fluoro-2,3-dihydro-benzofuran

Treatment of (S)-2-(3-bromo-2-hydroxy-propyl)-4-fluoro-phenol (1.97 g, 8 mmol), triphenylphosphine (5.2 g, 20 mmol), and diethylazodicarboxylate (3.11 ml, 20 mmol) generally according to the procedure described for Intermediate 18 afforded 1.40 g (76%) of (R)-2-bromomethyl-5-fluoro-2,3-dihydro-benzofuran as a colorless oil. HRMS ESI m/e 228.9661 [M−H]⁻. [α]_(D) ²⁵=−33.0 (c 1% in methanol).

Intermediate 241 (R)-2-Bromomethyl-5-methyl-2,3-dihydro-benzofuran

Treatment of (S)-2-(3-bromo-2-hydroxy-propyl)-4-methyl-phenol (5.0 g, 20 mmol) generally according to the procedure described for Intermediate 18 gave 3.04 g (70%) of (R)-2-bromomethyl-5-methyl-2,3-dihydro-benzofuran as a yellow oil. HRMS EI m/e 225.9998 (M)⁺; [α]_(D) ²⁵=−41.13 (c 8.86 in methanol).

Intermediate 242 (R)-2-Bromomethyl-2,3-dihydro-benzofuran

Treatment of (S)-2-(3-bromo-2-hydroxy-propyl)-phenol (2.71 g, 12 mmol) generally according to the procedure described for Intermediate 18 provided 1.62 g (65%) of (R)-2-bromomethyl-2,3-dihydro-benzofuran as a yellow oil. [α]_(D) ²⁵=−37 (c 1% in methanol); HRMS EI m/e 211.9840 (M)⁺, Calc'd. 211.9837.

Intermediate 243 (R)-2-Bromomethyl-7-(2′,6′-dichloro-phenyl)-5-fluoro-2,3-dihydro-benzofuran

Treatment of (S)-3-(3-bromo-2-hydroxy-propyl)-2′,6′-dichloro-5-fluoro-biphenyl-2-ol (1.48 g, 3.7 mmol) generally according to the procedure described for Intermediate 18 afforded 1.16 g (82%) of (R)-2-bromomethyl-7-(2′,6′-dichloro-phenyl)-5-fluoro-2,3-dihydro-benzofuran as a colorless oil. HRMS EI m/e 373.9277 (M)⁺, Calc'd. 373.9277; [α]_(D) ²⁵=−15.75 (c 8.0 in methanol).

Intermediate 244 (R)-7-Bromo-2-bromomethyl-5-fluoro-2,3-dihydrobenzofuran

To a solution of (R)-2-bromomethyl-5-fluoro-2,3-dihydro-benzofuran (3.20 g, 14 mmol) in acetic acid was added bromine (2.2 ml, 42 mmol) and the reaction mixture was allowed to stir at room temperature for 12 h. The solvent was removed in vacuo and the residue dissolved in dichloromethane and washed with saturated aqueous sodium sulfite. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 1:19) afforded 3.16 g (74%) of as a light yellow oil. HRMS EI m/e 307.8846 (M)⁺, Calc'd. 307.8848. [α]_(D) ²⁵=+24.8 (c 1% in methanol).

Intermediate 245 (R)-2-Bromomethyl-5-fluoro-7-o-toly-2,3-dihydrobenzofuran

Treatment of (R)-7-bromo-2-bromomethyl-5-fluoro-2,3-dihydrobenzofuran (2.57 g, 8.2 mmol) and o-tolyboronic acid (3.4 g, 24 mmol) generally according to the procedure described for Intermediate 37 afforded 2.54 g (95%) of (R)-2-Bromomethyl-5-fluoro-7-o-toly-2,3-dihydrobenzofuran as a colorless oil. HRMS EI m/e 320.0224 (M)⁺; [α]_(D) ²⁵=+35.00 (c 1% in methanol).

Intermediate 246 (R)-2-Bromomethyl-7-(2-chloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran

Treatment of (R)-7-bromo-2-bromomethyl-5-fluoro-2,3-dihydrobenzofuran (0.5 g, 1.6 mmol) and 2-chlorobenzene boronic acid (0.76 g, 4.8 mmol) generally according to the procedure described for Intermediate 37 gave 0.55 g (99%) (R)-2-bromomethyl-7-(2-chlorophenyl)-5-fluoro-2,3-dihydrobenzofuran as a colorless oil. HRMS EI M⁺ 339.9657; [α]_(D) ²⁵=+29.6 (c 8.14 in methanol).

Intermediate 247 (R)-2-Bromomethyl-7-(2-methyl-5-chloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran

Treatment of (R)-7-bromo-2-bromomethyl-5-fluoro-2,3-dihydrobenzofuran (0.40 g, 1.3 mmol) and 5-chloro-o-toluene boronic acid (0.88 g, 5.2 mmol) generally according to the procedure described for Intermediate 37 provided 0.41 g (90%) of (R)-2-bromomethyl-7-(2-methyl-5-chloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran as a colorless oil. HRMS EI M⁺ 353.9829; [α]_(D) ²⁵=+47.38 (c 9.29 in methanol).

Intermediate 248 (R)-2-Bromomethyl-7-(2-methyl-4-chloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran

Treatment of (R)-7-bromo-2-bromomethyl-5-fluoro-2,3-dihydrobenzofuran (0.42 g, 1.3 mmol) and 4-chloro-o-toluene boronic acid (0.88 g, 5.2 mmol) generally according to the procedure described for Intermediate 37 provided 0.43 g (95%) of (R)-2-bromomethyl-7-(2-methyl-4-chloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran as a colorless oil. HRMS EI M⁺ 353.9825, Calc'd. 353.9825; [α]_(D) ²⁵=+39.14 (c 7.0 in methanol).

Intermediate 249 (R)-2-Azidomethyl-7-(4-chloro-2-methyl-phenyl)-5-fluoro-2,3-dihydrobenzofuran

Treatment of (R)-2-Bromomethyl-7-(4-chloro-2-methyl-phenyl)-5-fluoro-2,3-dihydrobenzofuran (0.4 g, 1.1 mmol) generally according to the procedure described for Intermediate 98 gave 0.30 g (85%) of (R)-2-azidomethyl-7-(4-chloro-2-methyl-phenyl)-5-fluoro-2,3-dihydrobenzofuran as a colorless oil. HRMS EI m/e 317.0719 (M)⁺, Calc'd. 317.0718; [α]_(D) ²⁵=+16.76 (c 8.71 in methanol).

Intermediate 250 (R)-2-Azidomethyl-7-(5-chloro-2-methyl-phenyl)-5-fluoro-2,3-dihydrobenzofuran

Treatment of 2-bromomethyl-7-(5-chloro-2-methyl-phenyl)-5-fluoro-2,3-dihydroben-zofuran (0.41 g, 1.2 mmol) generally according to the procedure described for Intermediate 98 gave 0.31 g (85%) of (R)-2-azidomethyl-7-(5-chloro-2-methyl-phenyl)-5-fluoro-2,3-dihydrobenzofuran as a colorless oil. HRMS EI m/e 317.0734 (M)⁺, Calc'd. 317.0733; [α]_(D) ²⁵=+3.12 (c 7.71 in methanol).

EXAMPLE 1 (±)-1-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.36 g, 3.57 mmol) with sodium azide (0.929 g, 14.29 mmol) generally according to the procedure described for intermediate 98 afforded (±)-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. The azide was dissolved in ethanol (50 mL) and palladium on carbon (0.083 g, 10 wt. %) was added and the reaction mixture was shaken under an H₂ atmosphere (50 psi) for 6 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide a colorless oil. The oil was re-dissolved in isopropanol (3 mL) and hydrogen chloride (1.0 N in diethyl ether, 10.0 mL) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.700 g (94%) of (±)-1-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 229-230° C.; Anal. calcd. for C₁₅H₁₅NOHCl: C, 68.83; H, 6.16; N, 5.35. Found: C, 66.11; H, 6.25; N, 5.02.

EXAMPLE 2 (±)-1-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Fraction 1 (0.206 g) obtained from the chiral HPLC separation of (±)-benzyl (4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OD, ethanol:water 15:85) was treated with hydrogen bromide (3 mL, 30 wt. % in acetic acid) and the reaction mixture was allowed to stir at room temperature for 30 min. Diethyl ether (20 mL) was added to the reaction mixture and the resulting precipitate was filtered, washed with diethyl ether, and dried to afford 0.082 g (46%) of (+)-1-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a tan solid, hydrobromide salt. [α]_(D) ²⁵=+86.92 (c 10.0 in methanol); mp 225-226° C.; Anal. calcd. for C₁₅H₁₅NOHBr: C, 58.84; H, 5.27; N, 4.57. Found: C, 57.02; H, 4.96; N, 4.3.

EXAMPLE 3 (−)-1-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 0.197 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl (4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate, (Chiralcel OD, ethanol:water 15:85) with hydrogen bromide (3 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.091 g (54%) of (−)-1-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a tan solid, hydrobromide salt. [α]_(D) ²⁵=−84.76 (c 10.0 in methanol); mp 227-228° C.; Anal. calcd. for C₁₅H₁₅NOHBr: C, 58.84; H, 5.27; N, 4.57. Found: C, 57.19; H, 5.19; N, 4.18.

EXAMPLE 4 (±)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.31 g, 3.32 mmol) with sodium azide (0.863 g, 13.28 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-4-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.082 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.689 g (85%) of (±)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 231-234° C.; Anal. calcd. for C₁₆H₁₇NOHCl.0.2H₂O: C, 68.79; H, 6.64; N, 5.01. Found: C, 68.49; H, 6.50; N, 4.87.

EXAMPLE 5 (+)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.236 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, methanol) with hydrogen bromide (3 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.167 g (83%) of (+)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=+89.44 (c 10.0 in methanol); mp 232-233° C.; Anal. calcd. for C₁₆H₁₇NOHBr: C, 60.01; H, 5.67; N, 4.37. Found: C, 59.28; H, 5.36; N, 3.8.

EXAMPLE 6 (−)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.229 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, methanol) with hydrogen bromide (3 mL, 30 wt. % in acetic acid) according the procedure described for Example 2 afforded 0.190 g, (97%) of (−)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=−83.96 (c 10.0 in methanol); mp 231-233° C.; Anal. calcd. for C₁₆H₁₇NOHBr: C, 60.01; H, 5.67; N, 4.37. Found: C, 59.37; H, 5.64; N, 3.98.

EXAMPLE 7 (±)-1-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.00 g, 2.99 mmol) with sodium azide (0.78 g, 11.96 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-7-methoxy-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.06 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.465 g (54%) (±)-1-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 168-171° C.; Anal. calcd. for C₁₀H₁₃NO₂HCl: C, 55.69; H, 6.54; N, 6.49. Found: C, 55.68; H, 6.52; N, 6.5.

EXAMPLE 8 (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (4.08 g, 18.7 mmol) with p-toluenesulfonyl chloride (3.92 g, 21.9 mmol) in anhydrous pyridine (76 mL) generally according to the procedure described for Intermediate 10 gave (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a tan oil. Treatment of the tosylate with sodium azide (4.39 g, 67.57 mmol) generally according to the procedure described for Intermediate 98 afforded 4.1 g of (±)-2-(azidomethyl)-7-cyclopentyl-2,3-dihydro-1-benzofuran as a yellow oil. Treatment of the azide with palladium on carbon (0.41 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 2.5 g (58%) of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 174° C.; Anal. calcd. for C₁₄H₁₉ON₂HCl: C, 66.26; H, 7.94; N, 5.52. Found C, 66.13; H, 7.71; N, 5.5.

EXAMPLE 9 (−)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of 0.833 g of fraction 1 obtained from the chiral HPLC separation of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol:hexane 1:1) with hydrogen bromide (12.0 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.541 g (76%) of (−)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a tan solid, hydrobromide salt. [α]_(D) ²⁵=−13.4 (c 10.0 in methanol); mp 208-211° C.; Anal. calcd. for C₁₄H₁₉NOHBr: C, 56.39; H, 6.76; N, 4.7. Found: C, 55.83; H, 6.54; N, 4.41.

EXAMPLE 10 (+)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of 0.760 g of fraction 2 obtained from the chiral HPLC separation of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol:hexane 1:1) with hydrogen bromide (11.0 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 afforded 0.468 g (72%) of (+)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a tan solid, hydrobromide salt. [α]_(D) ²⁵=+11.5 (c 10.0 in methanol); Anal. calcd. for C₁₄H₁₉NOHBr: C, 56.39; H, 6.76; N, 4.7. Found: C, 56.03; H, 6.71; N, 4.63.

EXAMPLE 11 (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methanol (4.5 g, 0.017 mol) with p-toluenesulfonyl chloride (4.8 g, 0.025 mol), diisopropylethylamine (4.36 g, 0.034 mol), and 4-(dimethylamino)pyridine (0.12 g, 0.98 mmol) generally according to the procedure described for Intermediate 45 gave (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of the tosylate with sodium azide (4.03 g, 61.99 mmol) generally according to the procedure described for Intermediate 98 provided 3.45 g of (±)-2-(azidomethyl)-5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.75 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 2.70 g (60%) of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 210-213° C.; Anal. calcd for C₁₅H₂₀ClNOHCl: C, 59.61; H, 7.00; N, 4.63. Found: C, 57.29; H, 7.14; N, 4.78.

EXAMPLE 12 (±)-N-[(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methyl]-N-methylamine

To a suspension of lithium aluminum hydride (0.114 g, 3.0 mmol) in tetrahydrofuran (30 mL) was added (±)-methyl (5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (0.65 g, 2.0 mmol) and the reaction mixture was allowed to stir at room temperature for 30 h. The reaction mixture was quenched with saturated ammonium chloride (50 mL), diluted with tetrahydrofuran (70 mL), and the aqueous layer was extracted with tetrahydrofuran (2×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL), were dried (sodium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, dichloromethane:methanol 97:3) gave a light brown oil. The oil was re-dissolved in tetrahydrofuran (50 mL) and aqueous hydrogen chloride (1 N, 3 mL) was added. The resulting precipitate was filtered and washed with diethyl ether to provide 0.28 g (44%) of (±)-N-[(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methyl]-N-methylamine as a white solid, hydrochloride salt. mp 125-128° C.; Anal. calcd. for C₁₆H₂₂ClNOHCl: C, 60.76; H, 7.33; N, 4.43. Found: C, 60.92; H, 7.46; N, 4.09.

EXAMPLE 13 (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of 2-tert-butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol (18.25 g, 0.101 mol) with potassium carbonate (55.28 g, 0.400 mol) and allyl bromide (14.69 g, 0.121 mol) followed by treatment of the resultant allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-tert-butyl-4-methoxyphenol and 2-allyl-5-tert-butyl-4-methoxyphenol. Treatment of the phenol with 3-chloroperoxybenzoic acid (49.58 g, 0.287 mol, 77%) and potassium carbonate (33.0 g, 0.238 mol) generally according to the procedure described for Intermediate 9 gave 3.23 g (14%) of (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. Treatment of the benzofuran with p-toluenesulfonyl chloride (2.86 g, 0.015 mol) generally according to the procedure described for Intermediate 10 afforded (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (1.46 g, 22.5 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.14 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 1.5 g (40%) of (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylamine) as a white solid, hydrochloride salt. mp 174-176° C.; Anal calcd. for C₁₄H₂₁O₂NHCl: C, 61.87; H, 8.16; N, 5.15. Found C, 61.67; H, 8.37; N, 4.93.

EXAMPLE 14 (±)-[7-chloro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-chloro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.0 g, 2.46 mmol) with sodium azide (0.64 g, 9.83 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-7-chloro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.060 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.350 g (64%) of (±)-1-[7-chloro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C₁₀H₉F₃ClNOHCl: C, 41.69; H, 3.5; N, 4.86. Found: C, 41.78; H, 3.43; N, 4.77.

EXAMPLE 15 (±)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (6.53 g, 16.6 mmol) with sodium azide (4.30 g, 66.2 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. Treatment of the azide with palladium on carbon (0.40 g, 10 wt. %) generally according to the procedure described for Example 1 gave 3.62 g (79%) of (±)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 107-111° C. (dec); Anal. calcd. for C₁₆H₁₇NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 68.56; H, 6.66; N, 4.92.

EXAMPLE 16 (+)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 1.528 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl (7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OD, methanol) with palladium on carbon (0.15 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.781 g (69%) of (+)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+15.1 (c 10.0 in methanol); mp 128-131° C.; Anal. calcd. for C₁₆H₁₇NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 69.14; H, 6.51; N, 5.03.

EXAMPLE 17 (−)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 0.792 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl (7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OD, methanol) with palladium on carbon (0.08 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.415 g (71%) of (−)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−15.3 (c 10.0 in methanol); mp 128-131° C.; Anal. calcd. for C₁₆H₁₇NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 69.29; H, 6.59; N, 5.06.

EXAMPLE 18 (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.15 g, 14.9 mmol) with sodium azide (3.87 g, 59.5 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. Treatment of the azide with palladium on carbon (0.30 g, 10 wt. %) generally according to the procedure described for Example 1 gave 2.35 g (69%) of (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 160-164° C. (dec); Anal. calcd. for C₁₂H₁₇NOHCl: C, 63.29; H, 7.97; N, 6.15. Found: C, 63.33; H, 7.98; N, 6.15.

EXAMPLE 19 (−)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of 0.891 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl (7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol) with palladium on carbon (0.09 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.475 g (76%) of (−)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−34.09 (c 10.0 in methanol); mp 176-178° C.; Anal. calcd. for C₁₂H₁₇NOHCl: C, 63.29; H, 7.97; N, 6.15. Found: C, 63.32; H, 8.07; N, 6.14.

EXAMPLE 20 (+)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of 0.776 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl (7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol) with palladium on carbon (0.09 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.445 g (82%) of (+)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+32.18 (c 10.0 in methanol); mp 176-178° C.; Anal. calcd. for C₁₂H₁₇NOHCl: C, 63.29; H, 7.97; N, 6.15. Found: C, 63.86; H, 8.06; N, 6.00.

EXAMPLE 21 (±)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (6.64 g, 16.8 mmol) with sodium azide (3.28 g, 50.4 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran. To a solution of (±)-2-(azidomethyl)-5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran (4.44 g, 16.71 mmol) in tetrahydrofuran (100 mL) was added triphenylphoshine (5.25 g, 20.05 mmol) followed by water (10 mL) and the reaction mixture was allowed to stir at room temperature for 12 h. The solvent was removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, 10% ammonium hydroxide in methanol:ethyl acetate 1:9) provided a colorless oil. The oil was re-dissolved in isopropanol (5 mL) and hydrogen chloride (20.0 mL, 1.0 N in diethyl ether) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 4.08 g (88%) of (±)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp >225° C. (dec); Anal. calcd. for C₁₃H₁₈ClNOHCl: C, 56.53; H, 6.93; N, 5.07. Found: C, 56.56; H, 6.91; N, 4.94.

EXAMPLE 22 (−)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

To 1.61 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, ethanol) was added hydrogen bromide (20 mL, 30 wt. % in acetic acid) and the resulting solution was allowed to stir at room temperature for 3 h. The reaction mixture was diluted with water and neutralized with 2.0 N aqueous sodium hydroxide. The reaction mixture was extracted with ethyl acetate (2×100 mL), the combined organic layers were washed with water (100 mL) and saturated aqueous sodium chloride (100 mL), were dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, 10% aqueous ammonium hydroxide in methanol:ethyl acetate 1:9) provided a colorless oil. The oil was re-dissolved in isopropanol (2 mL) and hydrogen chloride (6 μL, 1.0 M in diethyl ether) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to give 0.52 g (44%) of (−)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−53.20 (c 10.0 in methanol); mp >225° C.; Anal. calcd. for C₁₃H₁₈ClNOHCl: C, 56.53; H, 6.93; N, 5.07. Found: C, 56.61; H, 7.06; N, 5.07.

EXAMPLE 23 (+)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 1.49 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, ethanol) with hydrogen bromide (20 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 22 afforded 0.456 g (42%) of (+)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+ 51.30 (c 10.0 in methanol); mp >225° C.; Anal. calcd. for C₁₃H₁₈ClNOHCl: C, 56.53; H, 6.93; N, 5.07. Found: C, 56.52; H, 7.06; N, 5.03.

EXAMPLE 24 (±)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (12.43 g, 0.035 mol) with sodium azide (6.73 g, 0.103 mol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-tert-butyl-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.750 g, 10 wt. %) generally according to the procedure described for Example 1 gave 5.56 g (67%) of (±)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 177-180° C. (dec); Anal. Calcd. for C₁₃H₁₉NOHCl: C, 64.59; H, 8.34; N, 5.79. Found: C, 64.34; H, 9.19; N, 5.73.

EXAMPLE 25 (−)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 1.31 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl (7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol) with palladium on carbon (0.13 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.747 g (80%) of (−)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−25.4 (c 10.0 in methanol); mp 178-180° C.; Anal. calcd. for C₁₃H₁₉NOHCl: C, 64.59; H, 8.34; N, 5.79. Found: C, 64.23; H, 8.75; N, 5.44.

EXAMPLE 26 (+)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 2.2 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl (7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol) with palladium on carbon (0.22 g, 10 wt. %) generally according to the procedure described for Example 1 gave 1.40 g (89%) of (+)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+24.99 (c 10.0 in methanol); mp 177-179° C.; Anal. calcd. for C₁₃H₁₉NOHCl: C, 64.59; H, 8.34; N, 5.79. Found: C, 64.87; H, 8.72; N, 5.51.

EXAMPLE 27 (±)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (13.74 g, 34.8 mmol) with sodium azide (9.05 g, 0.139 mol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran. Treatment of the azide with triphenylphoshine (9.13 g, 34.8 mmol) generally according to the procedure described for Example 21 afforded 4.43 (46 of (±)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 229-231° C.; Anal. calcd. for C₁₃H₁₈ClNOHCl: C, 56.53; H, 6.93; N, 5.07. Found: C, 56.49; H, 6.71; N, 4.86.

EXAMPLE 28 (−)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 0.888 g of fraction 1 obtained from the (±)-benzyl (7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, hexane:isopropanol 9:1) with hydrogen bromide (20 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.594 g (78%) of (−)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=−33.16 (c 10.0 in methanol); mp 219-222° C.; Anal. calcd. for C₁₃H₁₈ClNOHBr: C, 48.69; H, 5.97; N, 4.37. Found: C, 48.81; H, 6.01; N, 4.24.

EXAMPLE 29 (+)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 0.855 g of fraction 2 obtained from the (+)-benzyl (7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, hexane:isopropanol 9:1) with hydrogen bromide (20 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 provided 0.286 g (39%) of (+)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=+35.32 (c 10.0 in methanol); mp 219-222° C.; Anal. calcd. for C₁₃H₁₈ClNOHBr: C, 48.69; H, 5.97; N, 4.37. Found: C, 48.78; H, 5.97; N, 4.28.

EXAMPLE 30 (±)-1-(6-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(6-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.00 g, 2.99 mmol) with sodium azide (0.78 g, 11.96 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-6-methoxy-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.06 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.442 g (69%) of (±)-1-(6-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp >220° C.; Anal. calcd. for C₁₀H₁₃NO₂HCl: C, 55.69; H, 6.54; N, 6.49. Found: C, 55.29; H, 6.48; N, 6.38.

EXAMPLE 31 (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.280 g, 0.736 mmol) with sodium azide (0.191 g, 2.94 mmol) generally according to the procedure described for Intermediate 98 gave (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. Treatment of the azide with palladium on carbon (0.026 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.190 g (90%) of (±)-(6-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a tan solid, hydrobromide salt. mp 218-221° C. Anal. calcd. for C₁₅H₁₅NOHBr: C, 58.84; H, 5.27; N, 4.57. Found: C, 54.80; H, 4.88; N, 4.18.

EXAMPLE 32 (±)-1-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of {7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (0.75 g, 1.45 mmol) with sodium azide (0.24 g, 3.62 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (10%, 0.075 g) generally according to the procedure described for Example 1 afforded 0.270 g (47%) of (±)-1-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 174-175° C. (dec.); Anal. calcd. for C₁₇H₁₃F₆NOHCl: C, 51.34; H, 3.55; N, 3.52. Found: C, 51.25; H, 3.57; N, 3.68.

EXAMPLE 33 (±)-1-[7-(1-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 1-naphthaleneboronic acid (0.86 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.63 mmol) generally according to the procedure described for Intermediate 50 provided (±)-[7-(1-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.10 g, 1.49 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(1-naphthyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.03 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.10 g (10%) of (±)-1-[7-(1-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 120-124° C.; Anal. calcd. for C₁₉H₁₇NOHCl.0.5H₂O: C, 71.13; H, 5.97; N, 4.37. Found: C, 70.93; H, 5.74; N, 4.58.

EXAMPLE 34 (±)-1-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.68 g, 1.57 mmol) with sodium azide (0.25 g, 3.92 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.035 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.186 g (38%) of (±)-1-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >210° C.; Anal. calcd. for C₁₅H₁₃ClFNOHCl: C, 57.34; H, 4.49; N, 4.46. Found: C, 57.38; H, 4.32; N, 4.55.

EXAMPLE 35 (±)-1-[7-(3,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(3,5-dichlorophen yl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.22 g, 0.498 mmol) with sodium azide (0.08 g, 1.25 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(3,5-dichlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with triphenylphosphine (0.26 g, 0.997 mol) generally according to the procedure described for Example 21 afforded 0.08 g (49%) of (±)-1-[7-(3,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 165-168° C.; Anal. calcd. for C₁₅H₁₃Cl₂NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 54.27; H, 3.95; N, 4.23.

EXAMPLE 36 (±)-1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.06 mmol) with sodium azide (0.17 g, 2.65 mmol) generally according to the procedure described for Intermediate 98 provided (±)-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. Treatment of the azide with palladium on carbon (0.025 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.181 g (65%) of (±)-1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp >200° C. (dec); Anal. calcd. for C₁₅H₁₅NOHCl.0.2H₂O: C, 67.90; H, 6.23; N, 5.28. Found: C, 67.69; H, 6.16; N, 5.3.

EXAMPLE 37 (+)-(1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 0.40 g of fraction 1 obtained from the chiral HPLC separation of (±)-1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (Chiralpak AD, ethanol:hexane 1:1) with palladium on carbon (0.040 g, 10 wt. %) generally according to the procedure described for Example 1 gave (+)-(1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine 0.235 g (37%) as a white solid, hydrochloride salt. [α]_(D) ²⁵=+14.6 (c 10.0 in methanol); Anal. calcd. for C₁₅H₁₅NOHCl: C, 68.83; H, 6.16; N, 5.35. Found: C, 67.54; H, 5.97; N, 5.03.

EXAMPLE 38 (−)-1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 0.40 g of fraction 2 obtained from the chiral HPLC separation of (±)-1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (Chiralpak AD, ethanol:hexane 1:1) with palladium on carbon (0.040 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.212 g (33%) of (−)-1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−17.9 (c 10.0 in methanol); mp 220-222° C.; Anal. calcd. for C₁₅H₁₅NOHCl: C, 68.83; H, 6.16; N, 5.35. Found: C, 67.68; H, 6.07; N, 5.15.

EXAMPLE 39 (±)-1-[7-(2-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(2-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.51 g, 1.23 mmol) with sodium azide (0.20 g, 3.08 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-7-(2-naphthyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.050 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.183 g (48%) of (±)-1-[7-(2-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 135-140° C.; Anal. calcd. for C₁₉H₁₇NOHCl.0.3H₂O: C, 71.94; H, 5.91; N, 4.42. Found: C, 71.67; H, 5.95; N, 4.25.

EXAMPLE 40 (±)-1-(2′,3′-dihydro-2,7′-bi-1-benzofuran-2′-yl)methanamine

Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 2-benzofuranboronic acid (0.81 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.63 mmol) generally according to the procedure described for Intermediate 50 provided (±)-2′,3′-dihydro-2,7′-bi-1-benzofuran-2′-ylmethyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.09 g, 1.32 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2′-(azidomethyl)-2′,3′-dihydro-2,7′-bi-1-benzofuran. Treatment of the azide with palladium on carbon (0.03 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.12 g (12%) of (±)-1-(2′,3′-dihydro-2,7′-bi-1-benzofuran-2′-yl)methanamine as a white solid, hydrochloride salt. mp >220° C. (dec); Anal. calcd. for C₁₉H₁₇NOHCl.1.0H₂O: C, 63.85; H, 5.67; N, 4.38. Found: C, 63.54; H, 5.1; N, 4.3.

EXAMPLE 41 (±)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.90 g, 2.27 mmol) with sodium azide (0.44 g, 6.84 mmol) generally according to the procedure described for Intermediate 98 gave (+)-2-(azidomethyl)-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (10%, 0.060 g) generally according to the procedure described for Example 1 afforded 0.444 g (71%) of (±)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >210° C. (dec); Anal. calcd. for C₁₆H₁₇NOHCl 0.2H₂O: C, 68.79; H, 6.64; N, 5.01. Found: C, 68.54; H, 6.57; N, 4.9.

EXAMPLE 42 (+)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.390 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol:hexane 1:1) with palladium on carbon (0.039 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.189 g (66%) of (+)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+28.4 (c 10.0 in methanol); mp 196-198° C.; Anal. calcd. for C₁₆H₁₇NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 68.44; H, 6.71; N, 4.81.

EXAMPLE 43 (−)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.290 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol:hexane 1:1) with palladium on carbon (0.030 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.178 g (83%) of (−)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−25.6 (c 10.0 in methanol); mp 194-196° C.; Anal. calcd. for C₁₆H₁₇NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 68.92; H, 6.62; N, 4.94.

EXAMPLE 44 (±)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.2 g, 5.64 mmol) with sodium azide (1.48 g, 22.77 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. Treatment of the azide with palladium on carbon (0.130 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.838 g (55%) of (±)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp >200° C.; Anal. calcd. for C₁₃H₁₃FNOSHCl: C, 58.31; H, 5.27; N, 5.23. Found: C, 56.4; H, 5.23; N, 4.95.

EXAMPLE 45 (+)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 0.219 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl (7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel AD, water:methanol 1:9) with hydrogen bromide (3.0 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 afforded 0.120 g (64%) of (+)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a tan solid, hydrobromide salt. [α]_(D) ²⁵=+13.8 (c 10.0 in methanol); mp 234-236° C.; Anal. calcd. for C₁₃H₁₃NOSBBr: C, 50.01; H, 4.52; N, 4.49. Found: C, 49.37; H, 4.45; N, 4.41.

EXAMPLE 46 (−)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 0.211 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl (7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel AD, water:methanol 1:9) with hydrogen bromide (3.0 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.130 g (72%) of (−)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=−14.5 (c 10.0 in methanol); mp 234-235° C.; Anal. calcd. for C₁₃H₁₃NOSHBr: C, 50.01; H, 4.52; N, 4.49. Found: C, 49.15; H, 4.49; N, 4.38.

EXAMPLE 47 (±)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (7.79 g, 19.74 mmol) with sodium azide (5.13 g, 78.99 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.5 g, 10 wt. %) generally according to the procedure described for Example 1 provided 3.63 g (67%) of (±)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >200° C.; Anal. calcd. for C₁₆H₁₇NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 69.83; H, 6.64; N, 5.

EXAMPLE 48 (+)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 1.61 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, ethanol:hexane 1:1) with palladium on carbon (0.161 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.951 g (80%) of (+)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+16.9 (c 10.0 in methanol); mp 211-212° C.; Anal. calcd. for C₁₆H₁₇NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 68.88; H, 6.72; N, 4.92.

EXAMPLE 49 (−)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 1.68 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, ethanol:hexane 1:1) with palladium on carbon (0.169 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 1.04 g (84%) of (−)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−16.4 (c 10.0 in methanol); mp 208-209° C.; Anal. calcd. for C₁₆H₁₇NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 69.19; H, 6.62; N, 4.91.

EXAMPLE 50 (±)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.13 g, 7.85 mmol) with sodium azide (2.04 g, 31.42 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.21 g, 5 wt. %) generally according to the procedure described for Example 1 provided 1.81 g (83%) of (±)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 244-246° C.; Anal. calcd. for C₁₅H₁₄FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 63.98; H, 5.4; N, 4.89.

EXAMPLE 51 (+)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.542 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:isopropanol 9:1) with palladium on carbon (0.054 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.337 g (84%) of (+)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+7.14 (c 10.0 in dimethylsulfoxide); mp 227-228° C.; Anal. calcd. for C₁₅H₁₄FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 63.96; H, 5.4; N, 4.84.

EXAMPLE 52 (−)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.509 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:isopropanol 9:1) with palladium on carbon (0.050 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.318 g (84%) of (−)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−9.48 (c 10.0 in dimethylsulfoxide); mp 224-225° C.; Anal. calcd. for C₁₅H₁₄FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 63.74; H, 5.21; N, 4.91.

EXAMPLE 53 (±)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of (7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.0 g, 10.44 mmol) with 2-(trifluoromethyl)phenylboronic acid (2.57 g, 13.6 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.426 g, 0.542 mmol), and potassium carbonate (3.61 g, 26.09 mmol) generally according to the procedure described for Intermediate 37 provided (±)-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (1.31 g, 20.25 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.160 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.05 g (65%) of (±)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 204-205° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.25; H, 4.59; N, 4.25. Found: C, 57.57; H, 4.52; N, 4.08.

EXAMPLE 54 (−)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of 0.350 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate (Chiralcel OJ, ethanol:hexane 1:1) with palladium on carbon (0.035 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.200 g (74%) of (−)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−23.10 (c 10.0 in methanol); mp 109-111° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.09; H, 4.35; N, 4.21.

EXAMPLE 55 (+)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of 0.343 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate (Chiralcel OJ, ethanol:hexane 1:1) with palladium on carbon (0.034 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.165 g (62%) of (+)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+25.12 (c 10.0 in methanol); mp 97-100° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 57.82; H, 4.35; N, 4.15.

EXAMPLE 56 (±)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.646 g, 1.58 mmol) with sodium azide (0.411 g, 6.33 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.057 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.383 g (84%) of (±)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C₁₇H₁₉NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 69.06; H, 7.01; N, 4.21.

EXAMPLE 57 (−)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.524 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, methanol:carbon dioxide 3:7) with palladium on carbon (0.052 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.183 g (47%) of (−)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−3.98 (c 10.0 in methanol); mp 244-247° C.; Anal. calcd. for C₁₇H₁₉NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 69.61; H, 7.00; N, 4.60.

EXAMPLE 58 (+)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.530 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, methanol:carbon dioxide 3:7) with palladium on carbon (0.053 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.224 g (57%) of (+)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+4.28 (c 10.0 in methanol); mp 244-247° C.; Anal. calcd. for C₁₇H₁₉NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 69.61; H, 6.87; N, 4.65.

EXAMPLE 59 (±)-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2-methoxyphenylboronic acid (2.57 g, 16.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.532 g, 0.677 mmol), and potassium carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided (±)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.76 g, 11.69 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.072 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.453 g (12%) of (±)-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C₁₆H₁₇NO₂HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 65.72; H, 6.15; N, 4.86.

EXAMPLE 60 (±)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.6 g, 6.26 mmol) with sodium azide (1.63 g, 25.05 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.17 g, 5 wt. %) generally according to the procedure described for Example 1 provided 1.05 g (57%) of (±)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C₁₅H₁₄ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 60.71; H, 5.48; N, 4.55.

EXAMPLE 61 (±)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.81 g, 12.56 mmol) with 2-(2-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.63 g, 18.84 mmol, Intermediate 35), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.493 g, 0.627 mmol), and potassium carbonate (4.34 g, 31.38 mmol) generally according to the procedure described for Intermediate 37 provided (±)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (2.10 g, 32.37 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.22 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.15 g (56%) of (±)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine as a white solid, hydrochloride salt. mp 202-204° C.; Anal. calcd. for C₁₈H₂₁NOHCl: C, 71.16; H, 7.30; N, 4.61. Found: C, 70.83; H, 7.34; N, 4.48.

EXAMPLE 62 (+)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine

Treatment of 0.760 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 9:1) with palladium on carbon (0.076 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.388 g (63%) of (+)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+15.7 (c 10.0 in methanol); mp 205-206° C.; Anal. calcd. for C₁₈H₂₁NOHCl: C, 71.16; H, 7.3; N, 4.61. Found: C, 70.78; H, 7.42; N, 4.47.

EXAMPLE 63 (−)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine

Treatment of 0.749 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 9:1) with palladium on carbon (0.075 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.376 g (66%) of (−)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−16.0 (c 10.0 in methanol); mp 205-206° C.; Anal. calcd. for C₁₈H₂₁NOHCl: C, 71.16; H, 7.3; N, 4.61. Found: C, 70.54; H, 7.37; N, 4.61.

EXAMPLE 64 (±)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.68 g, 4.22 mmol) with sodium azide (1.09 g, 16.88 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.107 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.95 g (81%) of (±)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 200-202° C., Anal. calcd. for C₁₅H₁₄FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 63.93; H, 5.48; N, 4.73.

EXAMPLE 65 (±)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.6 g, 8.66 mmol) with sodium azide (2.25 g, 34.65 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.125 g, 5 wt. %) generally according to the procedure described for Example 1 provided 1.91 g (74%) of (±)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a tan solid, hydrochloride salt. mp 150-154° C.; Anal. calcd. for C₁₅H₁₄ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 59.17; H, 5.12; N, 4.38.

EXAMPLE 66 (+)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.495 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AS, hexane:isopropanol 9:1) with hydrogen bromide (6.2 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.150 g (28%) of (+)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a tan solid, hydrobromide salt. [α]_(D) ²⁵=+35.7 (c 10.0 in methanol); mp 187-189° C.; Anal. calcd. for C₁₅H₁₄ClNOHBr: C, 52.89; H, 4.44; N, 4.11. Found: C, 52.4; H, 4.47; N, 3.97.

EXAMPLE 67 (−)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.542 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AS, hexane:isopropanol 9:1) with hydrogen bromide (6-8 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 afforded 0.232 g (49%) of (−)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=−34.6 (c 10.0 in methanol); mp 189-190° C.; Anal. calcd. for C₁₅H₁₄ClNOHBr: C, 52.89; H, 4.44; N, 4.11. Found: C, 52.83; H, 4.47; N, 3.97.

EXAMPLE 68 (±)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.0 g, 7.82 mmol) with sodium azide (0.309 g, 4.48 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.030 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.25 g (80%) of (±)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 152-154° C.; Anal. calcd. for C₁₆H₁₇NO₂HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 65.21; H, 6.17; N, 4.46.

EXAMPLE 69 (±)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (5.2 g, 11.57 mmol) with sodium azide (3.01 g, 46.3 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.375 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.64 g (69%) of (±)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 172-174° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.09; H, 4.6; N, 4.03.

EXAMPLE 70 (±)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.01 g, 2.56 mmol) with sodium azide (0.664 g, 10.24 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.03 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.528 g (75%) of (±)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 231-232° C.; Anal. calcd. for C₁₆H₁₇NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 66.26; H, 7.0; N, 4.73.

EXAMPLE 71 (±)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.198 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, methanol:water 19:1)) with hydrogen bromide (3.0 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 afforded 0.143 g (84%) of (+)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a tan solid, hydrobromide salt. [α]_(D) ²⁵=+17.42 (c 10.0 in methanol); mp >250° C.; Anal. calcd. for C₁₆H₁₇NOHBr: C, 60.01; H, 5.67; N, 4.37. Found: C, 59.58; H, 5.57; N, 4.26.

EXAMPLE 72 (−)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.167 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, methanol:water 19:1) with hydrogen bromide (3.0 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.067 g (47%) of (−)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=−17.02 (c 10.0 in methanol); mp >250° C.; Anal. calcd. for C₁₆H₁₇NOHBr: C, 60.01; H, 5.67; N, 4.37. Found: C, 59.5; H, 5.67; N, 4.23.

EXAMPLE 73 (±)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.1 g, 3.01 mmol) with sodium azide (0.784 g, 12.04 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.074 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.542 g (64%) of (±)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 237-240° C.; Anal. calcd. for C₁₅H₁₄FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 64.26; H, 5.33; N, 4.85.

EXAMPLE 74 (+)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.184 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, methanol:water 19:1) with hydrogen bromide (2.0 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.08 g (55%) of (+)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=+ 13.26 (c 10.0 in methanol); mp 207-208° C.; Anal. calcd. for C₁₅H₁₄FNOHBr: C, 55.57; H, 4.66; N, 4.32. Found: C, 55.10; H, 4.59; N, 4.22.

EXAMPLE 75 (−)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.173 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, methanol:water 19:1) with hydrogen bromide (2.0 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 provided 0.108 g (73%) of (−)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=−12.24 (c 10.0 in methanol); mp 208-210° C.; Anal. calcd. for C₁₅H₁₄FNOHBr: C, 55.57; H, 4.66; N, 4.32. Found: C, 55.12; H, 4.62; N, 4.21.

EXAMPLE 76 (±)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.2 g, 2.89 mmol) with sodium azide (0.752 g, 11.57 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.082 g, 5 wt. %) generally according to the procedure described for Example 1 provided 0.592 g (69%) of (±)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 212-214° C.; Anal. calcd. for C₁₅H₁₄ClNOHCl: C, 60.83; H, 65.10; N, 4.73. Found: C, 59.99; H, 5.00; N, 4.47.

EXAMPLE 77 (+)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.226 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel AD, methanol) with hydrogen bromide (5.7 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.113 g (58%) of (+)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=+15.72 (c 10.0 in methanol); mp 229-231° C.; Anal. calcd. for C₁₅H₁₄ClNOHBr: C, 52.89; H, 4.44; N, 4.11. Found: C, 52.98; H, 4.43; N, 4.05.

EXAMPLE 78 (−)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.229 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel AD, methanol) with hydrogen bromide (5.8 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 provided 0.121 g (61%) of (−)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=−18.40 (c 10.0 in methanol); mp 233-235° C.; Anal. calcd. for C₁₅H₁₄ClNOHBr: C, 52.89; H, 4.44; N, 4.11. Found: C, 52.78; H, 4.4; N, 3.98.

EXAMPLE 79 (±)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.1 g, 5.11 mmol) with sodium azide (1.33 g, 20.96 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.125 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.860 g (58%) of (±)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 176-178° C.; Anal. calcd. for C₁₆H₁₇NO₂HCl: C, 65.86; H, 6.22; N, 4.80. Found: C, 65.02; H, 6.13; N, 4.57.

EXAMPLE 80 (+)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.314 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel AD, methanol) with palladium on carbon (0.031 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.160 g (68%) of (+)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+20.34 (c 10.0 in methanol); mp 183-186° C.; Anal. calcd. for C₁₆H₁₇NO₂HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 62.45; H, 6.11; N, 4.38.

EXAMPLE 81 (−)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.312 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate with hydrogen bromide (12.0 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 provided 0.156 g (58%) of (−)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=−14.66 (c 10.0 in methanol); mp 185-188° C.; Anal. calcd. for C₁₆H₁₇NO₂HBr: C, 57.16; H, 5.4; N, 4.17. Found: C, 56.53; H, 5.48; N, 4.01.

EXAMPLE 82 (±)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of (±)-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (3.3 g, 7.34 mmol) with sodium azide (1.91 g, 29.38 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.205 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.82 g (75%) of (±)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 57.47; H, 4.82; N, 3.65.

EXAMPLE 83 (±)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (4.2 g, 9.34 mmol) with sodium azide (2.4 g, 37.38 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.32 g, 5 wt. %) generally according to the procedure described for Example 1 provided 2.16 g (72%) of (±)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 198-200° C.; Anal. calcd. for C₁₅H₁₃Cl₂NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 54.5; H, 4.39; N, 4.16.

EXAMPLE 84 (±)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.55 g, 1.33 mmol) with sodium azide (0.345 g, 5.31 mmol) generally according to the procedure described for Intermediate 98 provided 0.35 g of (±)-2-(azidomethyl)-5-chloro-7-phenyl-2,3-dihydro-1-benzofuran as a colorless oil. Treatment of the azide with sulfided platinum on carbon (90 mg, 5 wt. %) generally according to the procedure described for Example 1 provided 0.14 g (40%) of (±)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 258° C. (dec); Anal. calcd. for C₁₅H₁₄ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 60.13; H, 4.95; N, 4.6.

EXAMPLE 85 (+)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (0.8 g, 2.70 mmol) with diisopropylethylamine (1.05 g, 8.10) and benzyl chloroformate (0.83 g, 4.86 mmol) generally according to the procedure described for Intermediate 12 afforded (±)-benzyl (5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate. Chiral HPLC separation of (±)-benzyl (5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, ethanol) provided two fractions. Fraction 1 (R_(t)=10.875 min, (Chiralpak AD, ethanol); Fraction 2 (R_(t)=15.590 min, (Chiralpak AD, ethanol). Treatment of 0.40 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl (5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, ethanol) with hydrogen bromide (5 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.27 g (77%) of (+)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=+0.7 (c 10.0 in methanol); mp 201-203° C.; Anal. calcd. for C₁₅H₁₄ClNOHBr: C, 52.89; H, 4.44; N, 4.11. Found: C, 52.96; H, 4.25; N, 3.88.

EXAMPLE 86 (−)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 0.23 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl (5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, ethanol) with hydrogen bromide (3 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.14 g (70%) of (−)-1-(5-chloro-7-phenyl-2,3-dihydro-1-12 benzofuran-2-yl)methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=−0.6 (c 10.0 in methanol); mp 201-203° C.; Anal. calcd. for C₁₅H₁₄ClNOHBr: C, 52.89; H, 4.44; N, 4.11. Found: C, 52.76; H, 4.38; N, 4.06.

EXAMPLE 87 (±)-1-[5-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.40 g, 2.88 mmol) with 2-chlorophenylboronic acid (0.67 g, 1.49 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.25 g, 0.30 mmol), and potassium carbonate (0.83 g, 6.0 mmol) generally according to the procedure described for Intermediate 35 provided (±)-[5-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (1.5 g, 23.1 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (120 mg, 5 wt. %) generally according to the procedure described for Example 1 gave 0.70 g (80%) of (±)-1-[5-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a yellow solid, hydrochloride salt. mp 231-234° C.; Anal. calcd. for C₁₅H₁₃Cl₂NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 46.01; H, 4.17; N, 3.25.

EXAMPLE 88 (±)-1-[5-chloro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-2-(azidomethyl)-5-chloro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran (0.26 g, 0.87 mmol) with sulfided platinum on carbon (85 mg, 5 wt. %) generally according to the procedure described for Example 1 afforded 0.14 g (59%) of (±)-1-[5-chloro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 268-271° C.; Anal. calcd. for C₁₆H₁₆ClNOHCl: C, 61.95; H, 5.52; N, 4.52. Found: C, 61.01; H, 5.44; N, 4.35.

EXAMPLE 89 (±)-1-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.00 g, 2.24 mmol) with sodium azide (0.93 g, 14.3 mmol) generally according to the procedure described for Intermediate 98 provided 0.41 g of (±)-2-(azidomethyl)-5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (100 mg, 5 wt. %) generally according to the procedure described for Example 1 provided 0.31 g (50%) of (±)-1-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 195° C. (dec); Anal. calcd for C₁₅H₁₃Cl₂NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 51.59; H, 4.21; N, 4.02.

EXAMPLE 90 (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.18 g, 0.43 mmol) with sodium azide (0.11 g, 1.72 mmol) generally according to the procedure described for Intermediate 98 provided 0.13 g of (±)-2-(azidomethyl)-5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (120 mg, 5 wt. %) generally according to the procedure described for Example 1 gave 0.11 g (85%) of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a light yellow solid, hydrochloride salt. mp 230° C. (dec); Anal. calcd. for C₁₃H₁₂ClNOSHCl: C, 51.66; H, 4.34; N, 4.63. Found: C, 45.27; H, 4.19; N, 3.93.

EXAMPLE 91 (−)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of 0.44 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl (5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, hexane:ethanol 1:1) with hydrogen bromide (5 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.20 g (52%) of (−)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=−6.00 (c 10.0 in dimethylsulfoxide); mp 277-280° C.; Anal. calcd. for C₁₃H₁₂ClNOSHBr: C, 45.04; H, 3.78; N, 4.04. Found: C, 44.67; H, 3.64; N, 3.84.

EXAMPLE 92 (+)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of 0.40 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl (5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, hexane:ethanol 1:1) with hydrogen bromide (5 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.31 g (89%) of (+)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=+5.01 (c 10.0 in dimethylsulfoxide); mp 277-280° C.; Anal. calcd. for C₁₃H₁₂ClNOSHBr: C, 45.04; H, 3.78; N, 4.04. Found: C, 44.88; H, 3.69; N, 3.86.

EXAMPLE 93 (+)-N-[(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]-N-methylamine

To a solution of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl (5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (0.50 g, 1.25 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (0.30 g, 7.5 mmol, 95 wt. %) and the reaction mixture was allowed to stir at room temperature for 5 h. The reaction mixture was quenched with ethyl acetate (5 mL) and partitioned between tetrahydrofuran (50 mL) and water (20 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL), was dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, dichloromethane:methanol 39:1) provided a light brown oil. The oil was re-dissolved in THF (50 mL), aqueous hydrogen chloride (1.0 N, 1.5 mL) was added, and the resulting precipitate was filtered and washed with diethyl ether (15 mL) to afford 0.14 g (35%) of (+)-N-[(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]-N-methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+6.6 (c 10.0 in methanol); mp 263-266° C.; Anal. calcd. for C₁₄H₁₄ClNOSHCl: C, 53.17; H, 4.78; N, 4.43. Found: C, 52.5; H, 4.88; N, 4.26.

EXAMPLE 94 (−)-N-[(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]-N-methylamine

Treatment of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl (5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (0.57 g, 1.43 mmol) with lithium aluminum hydride (0.30 g, 7.5 mmol, 95 wt. %) generally according to the procedure described for Example 93 afforded 0.26 g (58%) of (−)-N-[(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]-N-methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−8.2 (c 10.0 in methanol); mp 263-266° C.; Anal. calcd. for C₁₄H₁₄ClNOSHCl: C, 53.17; H, 4.78; N, 4.43. Found: C, 53.8; H, 4.85; N, 4.25.

EXAMPLE 95 (±)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.37 g, 2.81 mmol) with 2-methylphenylboronic acid (0.65 g, 4.60 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.25 g, 0.30 mmol), and potassium carbonate (0.83 g, 6.0 mmol) generally according to the procedure described for Intermediate 35 provided (±)-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (1.04 g, 16.1 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (200 mg, 5 wt. %) generally according to the procedure described for Example 1 gave 0.70 g (80%) of (±)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a light yellow solid, hydrochloric salt. mp 160-163° C.; Anal. calcd. for C₁₆H₁₆ClNOHCl: C, 61.95; H, 5.52; N, 4.52. Found: C, 57.75; H, 5.4; N, 3.95.

EXAMPLE 96 (+)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.65 g, 2.10 mmol) with diisopropylethylamine (0.813 g, 6.29) and benzyl chloroformate (0.71 g, 4.19 mmol) generally according to the procedure described for Intermediate 12 afforded (±)-benzyl[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate. Chiral HPLC separation of (±)-benzyl[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate. (Chiralpak AD, ethanol) provided two fractions. Fraction 1 (R_(t)=9.114 min, (Chiralpak AD, ethanol); Fraction 2 (R_(t)=11.426 min, (Chiralpak AD, ethanol). Treatment of 0.27 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl [5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol) with hydrogen bromide (5 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.22 g (94%) of (+)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrobromide salt.

[α]_(D) ²⁵=+1.5 (c 10.0 in methanol); mp 170-172° C.; Anal. calcd. for C₁₆H₁₆ClNOHBr: C, 54.18; H, 4.83; N, 3.95. Found: C, 53.28; H, 4.77; N, 3.66.

EXAMPLE 97 (−)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.25 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol) with hydrogen bromide (4 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.17 g (78%) of (−)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrobromide salt. [α]_(D) ²⁵=−1.6 (c 10.0 in methanol); mp 170-172° C.; Anal. calcd. for C₁₆H₁₆ClNOHBr: C, 54.18; H, 4.83; N, 3.95. Found: C, 53.01; H, 4.76; N, 3.78.

EXAMPLE 98 (±)-1-(4-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(4-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.03 g, 5.09 mmol) with sodium azide (1.32 g, 20.38 mmol) generally according to the procedure described for Intermediate 98 provided (+)-2-(azidomethyl)-4-fluoro-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.137 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.610 g (43%) of (±)-1-(4-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 254-257° C.; Anal. calcd. for C₁₅H₁₄FNOHCl: C, 64.4; H, 5.40; N, 5.01. Found: C, 64.98; H, 5.48; N, 4.79.

EXAMPLE 99 (±)-1-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.38 g, 3.35 mmol) with sodium azide (0.87 g, 13.38 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.083 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.561 g (57%) of (±)-1-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 228-231° C.; Anal. calcd. for C₁₆H₁₆FNOHCl: C, 65.42; H, 5.83; N, 4.77. Found: C, 66.01; H, 5.88; N, 4.51.

EXAMPLE 100 (±)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (6.65 g, 0.015 mol) with sodium azide (3.99 g, 0.061 mol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran. Treatment of the azide with triphenylphosphine (4.18 g, 0.16 mol) generally according to the procedure described for Example 21 provided 3.37 g (70%) of (±)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C. (dec); Anal. calcd. for C₁₅H₁₃ClFNOHCl: C, 57.34; H, 4.49; N, 4.46. Found: C, 57.45; H, 4.75; N, 4.22.

EXAMPLE 101 (+)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 1.22 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:ethanol 1:1) with hydrogen bromide (20 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 22, afforded 0.319 (34%) of (+)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+1.18 (c 10.0, methanol); mp 206-209° C.; Anal. calcd. for C₁₅H₁₃ClFNOHCl: C, 57.34; H, 4.49; N, 4.46. Found: C, 57.52; H, 4.67; N, 4.44.

EXAMPLE 102 (−)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 1.19 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:ethanol 1:1) with hydrogen bromide (20 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 22 provided 0.108 (12%) of (−)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 206-209° C.; FAB HRMS calcd. for C₁₅H₁₄ClFNO [M+H]⁺: 278.0748. Found m/z 278.0730.

EXAMPLE 103 (±)-1-(5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.76 mmol) with sodium azide (0.979 g, 15.06 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.101 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.719 g (68%) of (±)-1-(5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 255-260° C.; Anal. calcd. for C₁₅H₁₄FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 64.16; H, 5.54; N, 4.73.

EXAMPLE 104 (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.48 g, 3.59 mmol) with sodium azide (0.933 g, 14.35 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.101 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.555 g (53%) of (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 229-234° C.; Anal. calcd. for C₁₆H₁₆FNOHCl.0.1H₂O: C, 65.02; H, 5.87; N, 4.74. Found: C, 64.99; H, 5.83; N, 4.77.

EXAMPLE 105 (+)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 1.51 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 8:2) with palladium on carbon (0.151 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.981 g (87%) of (+)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+12.18 (c 10.0, methanol); mp 227-230° C.; Anal. calcd. for C₁₆H₁₆FNOHCl: C, 65.42; H, 5.83; N, 4.77. Found: C, 65.11; H, 5.78; N, 4.62.

EXAMPLE 106 (−)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 1.65 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 4:1) with palladium on carbon (0.133 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.966 g (78%) of (−)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−11.4 (c 10.0, methanol); mp 227-230° C.; Anal. calcd. for C₁₆H₁₆FNOHCl: C, 65.42; H, 5.83; N, 4.77. Found: C, 65.28; H, 5.78; N, 4.66.

EXAMPLE 107 (±)-1-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.84 g, 4.42 mmol) with sodium azide (1.15 g, 17.67 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.111 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.02 g (77%) of (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 240-247° C. (dec); Anal. calcd. for C₁₅H₁₃F₂NOHCl: C, 60.51; H, 4.74; N, 4.7. Found: C, 60.33; H, 4.69; N, 4.4.

EXAMPLE 108 (±)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of (±)-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (5.34 g, 0.011 mol) with sodium azide (2.60 g, 0.04 mol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with triphenylphosphine (2.89 g, 0.011 mol) generally according to the procedure described for Example 21 afforded 3.25 g (89%) of (±)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 196-198° C. (dec); Anal. calcd. for C₁₆H₁₃F₄NOHCl: C, 55.26; H, 4.06; N, 4.03. Found: C, 55.88; H, 4.26; N, 3.77.

EXAMPLE 109 (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide (0.60 g, 2.09 mmol) in methanol (40 mL) with sulfided platinum on carbon (0.15 g, 5 wt. %) generally according to the procedure described for Example 1 provided 0.60 g (96%) of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a pink solid, hydrochloride salt. mp >240° C.; Anal. calcd. for C₁₅H₁₃F₂NOHCl0.5H₂O: C, 58.74; H, 4.93; N, 4.57. Found: C, 58.6; H, 4.56; N, 4.33.

EXAMPLE 110 (±)-1-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide (0.85 g, 2.82 mmol) with sulfided platinum on carbon (0.30 g, 5 wt. %) generally according to the procedure described for Example 1 gave 0.78 g (67%) of (±)-1-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a grey solid, hydrochloride salt. mp >224-227° C.; Anal. calcd. for C₁₆H₁₅F₂NOHCl.0.4H₂O: C, 60.25; H, 5.31; N, 4.39. Found: C, 59.98; H, 5.33; N, 4.39.

EXAMPLE 111 (±)-1-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.10 g, 2.98 mmol) with sodium azide (1.5 g, 23.1 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-5-chloro-7-methoxy-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.080 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 0.415 g (56%) of (±)-1-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 195-198° C.; Anal. calcd. for C₁₀H₁₂ClNO₂HCl: C, 48.02; H, 5.24; N, 5.6. Found: C, 46.41; H, 5.09; N, 5.31.

EXAMPLE 112 (±)-1-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of (±)-(5-chloro-2-methyl-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 10.0 mmol) with phenylboronic acid (1.83 g, 15.0 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.82 g, 1.0 mmol), and potassium carbonate (2.76 g, 20.0 mmol) generally according to the procedure described for Intermediate 35 gave (±)-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of (±)-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.1 g, 9.5 mmol) with sodium azide (3.9 g, 60.0 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.350 g, 5 wt. %) generally according to the procedure described for Example 1 provided 2.0 g (64%) of (±)-1-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 222-225° C.; Anal. calcd. for C₁₆H₁₆ClNOHCl: C, 61.95; H, 5.52; N, 4.52. Found: C, 60.82; H, 5.67; N, 4.37.

EXAMPLE 113 (±)-(5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of (±)-(5-chloro-2-methyl-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 10.0 mmol), thiophene-3-boronic acid (1.92 g, 15.0 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.82 g, 1.0 mmol), and potassium carbonate (2.76 g, 20.0 mmol) generally according to the procedure described for Intermediate 35 provided (±)-(5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (2.00 g, 30.7 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.250 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 0.7 g (22%0 of (±)-(5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 295-298° C. (dec); Anal. calcd. for C₁₄H₁₄ClNOSHCl: C, 53.17; H, 4.78; N, 4.43. Found: C, 52.80; H, 4.74; N, 4.24.

EXAMPLE 114 (±)-(5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine

Treatment of (±)-(5-chloro-2-methyl-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.90 g, 5.8 mmol), thiophene-2-boronic acid (1.11 g, 8.7 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.47 g, 0.58 mmol), and potassium carbonate (1.6 g, 11.6 mmol) generally according to the procedure described for Intermediate 35 gave (±)-(5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (2.00 g, 30.7 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.250 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 0.58 g of (±)-(5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 251-252° C.; Anal. calcd. for C₁₄H₁₄ClNOSHCl: C, 53.17; H, 4.78; N, 4.43. Found: C, 51.17; H, 4.48; N, 4.32.

EXAMPLE 115 (−)-1-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 0.211 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl (7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (R_(t)=4.39 min, Chiralpak OD, 2-butanol:carbon dioxide 2:8) with palladium on carbon (0.021 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.098 g (63%) of (−)-1-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 157-159° C.; [α]_(D) ²⁵=−32.46 (c 10.0 in methanol); Anal. calcd. for C₁₄H₂₁NO₂HCl: C, 61.87; H, 8.16; N, 5.15. Found: C, 59.03; H, 7.86; N, 4.77.

EXAMPLE 116 (+)-1-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine

Treatment of 0.264 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl [(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl]carbamate (R_(t)=5.07 min, Chiralpak OD, 2-butanol:carbon dioxide 2:8) with palladium on carbon (0.026 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.098 g (50%) of (±)-1-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+31.9 (c 10.0 in methanol); mp 157-159° C.; Anal. calcd. for C₁₄H₂₁NO₂HCl: C, 61.87; H, 8.16; N, 5.15. Found: C, 60.04; H, 8.09; N, 4.78.

EXAMPLE 117 (±)-1-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of (±)-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (6.54 g, 16.92 mmol) with sodium azide (4.37 g, 67.68 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide. Treatment of the azide (1.78 g, 6.92 mmol) with triphenylphosphine (1.81 g, 6.92 mmol) generally according to the procedure described for Example 21 afforded 0.454 g (28%) of (±)-1-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 216-218° C.; Anal. calcd. for C₁₅H₂₁NOHCl: C, 67.28; H, 8.28; N, 5.23. Found: C, 66.19; H, 8.27; N, 5.14.

EXAMPLE 118 (±)-1-[7-(3,3-dimethylbutyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide (1.82 g, 7.07 mmol) with palladium on carbon (0.18 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.642 g (34%) of (±)-1-[7-(3,3-dimethylbutyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 158-160° C.; Anal. calcd. for C₁₅H₂₃NOHCl: C, 66.77; H, 8.97; N, 5.19. Found: C, 66.31; H, 8.56; N, 5.09.

EXAMPLE 119 (±)-1-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of (±)-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (6.53 g, 16.06 mmol) with sodium azide (4.17 g, 64.25 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide. Treatment of (±)-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide (2.2 g, 7.9 mmol) with triphenylphosphine (2.08 g, 7.9 mmol) generally according to the procedure described for Example 21 afforded 0.675 g (34%) of (±)-1-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 209-211° C.; Anal. calcd. for C₁₇H₁₇NOHCl: C, 70.95; H, 6.3; N, 4.87. Found: C, 69.63; H, 6.46; N, 4.72.

EXAMPLE 120 (±)-1-[7-(2-phenylethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide (2.2 g, 7.9 mmol) with palladium on carbon (0.22 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.1 g (48%) of (±)-1-[7-(2-phenylethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 155-157° C.; Anal. calcd. for C₁₇H₁₉NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 70.11; H, 7.08; N, 4.62.

EXAMPLE 121 (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.0 mmol), o-tolylboronic acid (2.66 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.651 mmol), and potassium carbonate (4.51 g, 32.63 mmol) generally according to the procedure described for Intermediate 37 provided 4.0 g (77%) of (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a yellow oil. Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (3.8 g, 9.63 mmol) with sodium azide (2.5 g, 38.53 mmol) generally according to the procedure described for Intermediate 98 gave 2.39 g (94%) of [4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.239 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.3 g (93%) of (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 239-241° C.; Anal. calcd. for C₁₆H₁₇NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 69.36; H, 6.64; N, 4.93.

EXAMPLE 122 (±)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2-(trifluoromethyl)phenylboronic acid (3.72 g, 17.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 4.5 g (77%) of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (4.3 g, 9.59 mmol) with sodium azide (2.5 g, 38.46 mmol) generally according to the procedure described for Intermediate 98 gave 2.88 g (94%) of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide. Treatment of the azide with palladium on carbon (0.28 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.46 g (83%) of (±)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 213-215° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.13; H, 4.65; N, 4.13.

EXAMPLE 123 (−)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of 0.825 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (R_(t)=5.701 min, Chiralcel OJ, ethanol:hexane 1:1) with palladium on carbon (0.082 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.480 g (76%) of (−)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−81.36 (c 10.0 in methanol); mp 203-206° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.12; H, 5.15; N, 3.92.

EXAMPLE 124 (+)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of 0.800 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (R_(t)=7.122 min, Chiralcel OJ, ethanol:hexane 1:1) with palladium on carbon (0.080 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.334 g (54%) of (−)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+79.42 (c 10.0 in methanol); mp 203-206° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 57.98; H, 5.36; N, 3.85.

EXAMPLE 125 (±)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.27 g, 5.55 mmol) with sodium azide (1.44 g, 22.23 mmol) generally according to the procedure described for Intermediate 98 gave 1.41 g (91%) of (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.141 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.36 g (93%) of (±)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 254-256° C.; Anal. calcd. for C₁₇H₁₉NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 69.03; H, 7.05; N, 4.66.

EXAMPLE 126 (+)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.564 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=4.818 min, Chiralcel OD, ethanol) with palladium on carbon (0.056 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.321 g (76%) of (+)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+89.54 (c 10.0 in methanol); mp >250° C.; Anal. calcd. for C₁₇H₁₉NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 68.75; H, 7.1; N, 4.32.

EXAMPLE 127 (−)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.372 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (R_(t)=6.985 min, Chiralcel OD, ethanol) with palladium on carbon (0.037 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.275 g (99%) of (−)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−91.76 (c 10.0 in methanol); mp >250° C.; Anal. calcd. for C₁₇H₁₉NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 68.59; H, 6.85; N, 4.48.

EXAMPLE 128 (+)-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.928 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 9:1) with palladium on carbon (0.092 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.549 g (75%) of (+)-1-[7-(2-methoxyphenyl) 2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+9.90 (c 10.0 in methanol); mp 180-184° C.; Anal. calcd. for C₁₆H₁₇NO₂HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 64.46; H, 6.24; N, 4.63.

EXAMPLE 129 (−)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

To a solution of (+)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.530 g, 1.34 mmol) in acetonitrile (25 mL) cooled to 0° C. was added iodotrimethylsilane (1.07 g, 5.38 mmol) and the reaction mixture was allowed to stir for 90 min. The reaction mixture was quenched by the addition of aqueous hydrogen chloride (25 mL, 2.0 N) and washed with diethyl ether (50 mL). The aqueous layer was neutralized with aqueous sodium hydroxide (50 mL, 2.5 N) and extracted with dichloromethane (2×100 mL). The combined organic fractions were washed with water (75 mL), saturated aqueous sodium chloride (50 mL), dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. The oil was re-dissolved in isopropanol (2 mL) and hydrogen chloride (5.0 mL, 1.0 M in diethyl ether) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.229 g (58%) of (−)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−11.06 (c 10.0 in dimethylsulfoxide); mp 186-188° C.; Anal. calcd. for C₁₅H₁₄ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found C, 59.59; H, 5.13; N, 4.48.

EXAMPLE 130 (+)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (−)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.480 g, 1.22 mmol) with iodotrimethylsilane (0.975 g, 4.87 mmol) generally according to the procedure described for Example 129 afforded 0.272 g (75%) of (+)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+9.90 (c 10.0 in dimethylsulfoxide); mp 186-188° C.; Anal. calcd. for C₁₅H₁₄ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found C, 60.53; H, 5.39; N, 4.62.

EXAMPLE 131 (+)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (+)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.326 g, 0.864 mmol) with palladium on carbon (0.033 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.195 g (81%) of (+)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+18.32 (c 10.0 in methanol); mp 186-188° C.; Anal. calcd. for C₁₅H₁₄FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 63.32; H, 5.1; N, 4.86.

EXAMPLE 132 (−)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (−)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.330 g, 0.874 mmol) with palladium on carbon (0.033 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.135 g (55%) of (−)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−19.00 (c 10.0 in methanol); mp 186-188° C.; Anal. calcd. for C₁₅H₁₄FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 63.52; H, 5.16; N, 4.91.

EXAMPLE 133 (+)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (+)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (1.36 g, 3.49 mmol) with palladium on carbon (0.136 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.70 g (79%) of (+)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ⁵=+32.44 (c 10.0 in methanol); mp 156-158° C.; Anal. calcd. for C₁₆H₁₇NO₂HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 65.25; H, 6.18; N, 4.69.

EXAMPLE 134 (−)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (−)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (1.38 g, 3.54 mmol) with palladium on carbon (0.138 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.558 g (62%) of (−)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−32.14 (c 10.0 in methanol); mp 156-158° C.; Anal. calcd. for C₁₆H₁₇NO₂HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 65.03; H, 6.22; N, 4.7.

EXAMPLE 135 (−)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of 0.680 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl({7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (Chiralpak OJ, isopropanol:carbon dioxide 15:85) with palladium on carbon (0.068 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.301 g (67%) of (−)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−31.74 (c 10.0 in methanol); mp 184-186° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.15; H, 4.57; N, 4.21.

EXAMPLE 136 (+)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of 0.700 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl({7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (Chiralpak OJ, isopropanol:carbon dioxide 15:85) with palladium on carbon (0.070 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.328 g (61%) of (+)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+31.66 (c 10.0 in methanol); mp 184-186° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 57.96; H, 4.44; N, 4.16.

EXAMPLE 137 (+)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of 0.720 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl({7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate

(Chiralpak AD, methanol:water 95:5) with palladium on carbon (0.072 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.411 g (74%) of (+)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+15.90 (c 10.0 in methanol); mp 226-229° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 57.31; H, 4.84; N, 4.09.

EXAMPLE 138 (−)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of 0.740 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl({7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (Chiralpak AD, methanol:water 95:5) with palladium on carbon (0.074 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.425 g (74%) of (−)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−14.98 (c 10.0 in methanol); mp 226-229° C.; Anal. calcd. for C₁₆H₁₄F₃NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 57.48; H, 4.51; N, 4.09.

EXAMPLE 139 (±)-1-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (3.5 g, 13.35 mmol) with p-toluenesulfonyl chloride (3.05 g, 16.01 mol) generally according to the procedure described for Intermediate 10 gave 3.5 g (64%) of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.0 g, 7.20 mmol) with sodium azide (1.87 g, 28.8 mmol) generally according to the procedure described for Intermediate 98 gave (±)-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.20 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.69 g (90%) of (±)-1-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 219-222° C.; Anal. calcd. for C₁₅H₁₃F₂NOHCl: C, 60.51; H, 4.74; N, 4.7. Found: C, 60.34; H, 4.87; N, 4.58.

EXAMPLE 140 (±)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.75 g, 1.67 mmol) with sodium azide (0.43 g, 6.67 mmol) generally according to the procedure described for Intermediate 98 afforded 0.48 g (90%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with triphenylphosphine (0.393 g, 1.49 mmol) generally according to the procedure described for Example 21 afforded 0.348 g (71%) of (±)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 206-208° C.; Anal. calcd. for C₁₅H₁₃Cl₂NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 54.38; H, 4.36; N, 4.12.

EXAMPLE 141 (−)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.081 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak AD, ethanol:hexane 1:1) with iodotrimethylsilane (0.153 g, 0.766 mmol) generally according to the procedure described for Example 129 gave 0.039 g (58%) of (−)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−29.8 (c 10.0 in dimethylsulfoxide); mp 207-209° C.; Anal. calcd. for C₁₅H₁₃Cl₂NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 54.74; H, 3.97; N, 4.23.

EXAMPLE 142 (+)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.132 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak AD, ethanol:hexane 1:1) with iodotrimethylsilane (0.247 g, 1.23 mmol) generally according to the procedure described for Example 129 gave 0.036 g (56%) of (+)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+30.0 (c 10.0 in dimethylsulfoxide); mp 207-209° C.; Anal. calcd. for C₁₅H₁₃Cl₂NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 54.43; H, 4.017; N, 4.19.

EXAMPLE 143 (±)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.0 g, 6.81 mmol) with sodium azide (1.77 g, 27.26 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.215 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.57 g (72%) of (±)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 175-178° C.; Anal. calcd. for C₁₇H₁₉NO₃HCl: C, 63.45; H, 6.26; N, 4.35. Found: C, 62.59; H, 6.25; N, 4.01.

EXAMPLE 144 (−)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (+)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.660 g, 1.57 mmol) with palladium on carbon (0.066 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.242 g (48%) of (−)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a pale yellow solid, hydrochloride salt. [α]_(D) ²⁵=−4.7 (c 10.0 in methanol); mp 166-168° C.; Anal. calcd. for C₁₇H₁₉NO₃HCl: C, 63.45; H, 6.26; N, 4.35. Found: C, 60.84; H, 6.51; N, 3.98.

EXAMPLE 145 (+)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (−)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.638 g, 1.52 mmol) with palladium on carbon (0.066 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.357 g (73%) of (+)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a pale yellow solid, hydrochloride salt. [α]_(D) ²⁵=+1.16 (c 10.0 in methanol); mp 166-168° C.; Anal. calcd. for C₁₇H₁₉NO₃HCl: C, 63.45; H, 6.26; N, 4.35. Found: C, 61.94; H, 6.85; N, 3.76.

EXAMPLE 146 (±)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (4.3 g, 10.37 mmol) with sodium azide (3.03 g, 46.68 mmol) generally according to the procedure described for Intermediate 98 gave 2.91 g (98%) of (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.29 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 2.3 g (76%) of (±)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 222-224° C.; Anal calcd. for C₁₅H₁₃F₂NOHCl: C, 60.51; H, 4.74; N, 4.7. Found C, 60.65; H, 4.76; N, 4.51.

EXAMPLE 147 (+)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (+)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (1.1 g, 2.78 mmol) with palladium on carbon (0.135 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.312 g (43%) of (+)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+3.58 (c 10.0 in dimethylsulfoxide); mp 222-224° C.; Anal. calcd. for C₁₅H₁₃F₂NOHCl: C, 60.51; H, 4.74; N, 4.7. Found: C, 59.98; H, 4.7; N, 4.64.

EXAMPLE 148 (−)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (−)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.612 g, 1.55 mmol) with palladium on carbon (0.061 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.268 g (66%) of (−)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−4.66 (c 10.0 in dimethylsulfoxide); mp 222-224° C.; Anal. calcd. for C₁₅H₁₃F₂NOHCl: C, 60.51; H, 4.74; N, 4.7. Found: C, 60.34; H, 4.58; N, 4.48.

EXAMPLE 149 (−)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (+)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (2.06 g, 4.81 mmol) with iodotrimethylsilane (3.85 g, 19.24 mmol) generally according to the procedure described for Example 129 gave 0.933 g (85%) of (−)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−3.34 (c 10.0 in dimethylsulfoxide); mp 203-206° C.; Anal. calcd. for C₁₅H₁₃Cl₂NOHCl: C, 54.59; H, 4.27; N, 4.24. Found: C, 53.69; H, 3.96; N, 3.99.

EXAMPLE 150 (+)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (−)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (1.85 g, 4.32 mmol) with iodotrimethylsilane (3.45 g, 17.28 mmol) generally according to the procedure described for Example 129 gave 1.04 g (82%) of (+)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+2.7 (c 10.0 in dimethylsulfoxide); mp 201-204° C.; Anal. calcd. for C₁₅H₁₃Cl₂NOHCl: C, 54.59; H, 4.27; N, 4.24. Found: C, 54.25; H, 4.12; N, 4.16.

EXAMPLE 151 (−)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of 0.837 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl({5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (R_(t)=4.965 min, Chiralcel AD, methanol) with iodotrimethylsilane (1.50 g, 7.51 mmol) generally according to the procedure described for Example 129 gave 0.301 g (51%) of (−)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−20.00 (c 10.0 in methanol); mp 183-188° C.; Anal. calcd. for C₁₆H₁₃F₄NOHCl: C, 55.26; H, 4.06; N, 4.03. Found: C, 53.42; H, 4.1; N, 4.4.

EXAMPLE 152 (+)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine

Treatment of 0.751 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl({5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (R_(t)=6.877 min, Chiralcel AD, methanol) with iodotrimethylsilane (0.675 g, 3.37 mmol) generally according to the procedure described for Example 129 gave 0.211 g (36%) of (+)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+18.98 (c 10.0 in methanol); mp 193-197° C.; Anal. calcd. for C₁₆H₁₃F₄NOHCl: C, 55.26; H, 4.06; N, 4.03. Found: C, 51.01; H, 3.76; N, 4.14.

EXAMPLE 153 No Compound EXAMPLE 154 (±)-1-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,3-dimethyl-phenyl)boronic acid (0.294 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.041 g, 0.052 mmol), and potassium carbonate (0.41 g, 3.25 mmol) generally according to the procedure described for Intermediate 37 provided 0.335 g (62%) of (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate with sodium azide (0.134 g, 2.06 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-7 amine. To a solution of (±)-2-(azidomethyl)-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-7 amine (0.135 g, 1.483 mmol) in tetrahydrofuran (5 mL) was added polymer supported triphenyl phosphine (0.152 g, 0.58 mmol) and the reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide a colorless oil. The oil was re-dissolved in isopropanol (3 mL) and hydrogen chloride (1.0 N in diethyl ether, 10.0 mL) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.075 g (54%) of (±)-1-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >225° C.

EXAMPLE 155 (±)-{[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared following the general procedure of Example 154 as a light yellow solid (2.91 g, 58%) from (O)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (6.0 g, 15.65 mmol) and (2,3-dimethoxyphenyl)boronic acid (4.27 g, 23.49 mmol). mp 219-222° C.

EXAMPLE 156 (−)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 1.46 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate Chiralcel OD, 2-butanol:carbon dioxide 3:7 with palladium on carbon (0.146 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.767 g (69%) of (−)-{[(−7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a tan solid, hydrochloride salt. [α]_(D) ²⁵=−65.6 (c 10.0 in methanol); mp 146-148° C.

EXAMPLE 157 (+)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 1.45 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate Chiralcel OD, 2-butanol:carbon dioxide 3:7 with palladium on carbon (0.146 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.86 g (77%) of (+)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+61.6 (c 10.0 in methanol); mp 146-148° C.

EXAMPLE 158 (+)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of fraction 1 (0.437 g) obtained from the chiral HPLC separation of (±)-benzyl {[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel AD, ethanol:hexane 1:10) in acetonitrile (25 mL) was cooled to 0° C. and treated with iodotrimethylsilane (0.883 g, 4.413 mmol) and the reaction mixture was allowed to stir at for 1 h. The solvent was removed in vacuo and the residue quenched with aqueous hydrogen chloride (2.0 N) (300 mL) and washed with diethyl ether (300 mL). The aqueous layer was separated, treated with 10% potassium hydroxide and dichloromethane (600 mL). The combined organic layers were washed with water (200 mL) and saturated aqueous sodium chloride (200 mL), was dried (magnesium sulfate), and the solvent was removed in vacuo to provide 0.20 g (60%) of (+) {[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine (0.437 g, 1.07 mmol) as a white solid, hydrochloride salt. [α]_(D) ²⁵=+10.2 (c 10.0 in methanol); mp 190-191° C.

EXAMPLE 159 (−)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.224 g, 74%) following the general procedure of Example 158 as a white solid, hydrochloride salt from (−)-benzyl {[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.40 g, 0.981 mmol) and iodotrimethylsilane (0.785 g, 3.92 mmol). [α]_(D) ²⁵=−13.0 (c 10.0 in methanol); mp 190-191° C.

EXAMPLE 160 (±)-{[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.051 g, 26%) following the general procedure of Example 154 as a light yellow solid, hydrochloride salt from (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmol) and (2,3-difluorophenyl)boronic acid (0.618 g, 3.91 mmol). mp 219-222° C.

EXAMPLE 161 (±)-{[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.075 g, 40%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmol) and (2,5-dimethylphenyl)boronic acid (0.618 g, 3.91 mmol). mp >225° C.

EXAMPLE 162 (±)-{[7-(2,5-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.043 g, 35%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmol) and (2,5-dimethoxyphenyl)boronic acid (0.356 g, 1.96 mmol). mp 128-132° C.

EXAMPLE 163 (±)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.56 g, 45%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.43 g, 1.31 mmol) and (2,5-dichlorophenyl)boronic acid (1.07 g, 5.59 mmol). mp 203-205° C.

EXAMPLE 164 (+)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.771 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (1.44 g, 7.20 mmol) generally according to the procedure described for Example 158 gave 0.202 g (59%) of (+)-{[(7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt [α]_(D) ²⁵=+16.0 (c 10.0 in methanol); mp 181-183° C.

EXAMPLE 165 (−)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.710 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (1.33 g, 6.63 mmol) generally according to the procedure described for Example 158 gave 0.202 g (45%) of (−)-{[(−7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−14.4 (c 10.0 in methanol); mp 184-186° C.

EXAMPLE 166 (±)-{[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 2,4,6-trichlorobromobenzene (14.5 g, 55.69 mmol) with 2-methoxybenzeneboronic acid (12.69 g, 83.54 mol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.656 g, 0.835 mmol), and potassium carbonate (19.21 g, 139.22 mmol) generally according to the procedure described for Intermediate 37 provided 9.8 g (61%) of 2′,4′,6′-trichloro-1,1′-biphenyl-2-yl methyl ether. To a solution of 2′,4′,6′-trichloro-1,1′-biphenyl-2-yl methyl ether (9.8 g, 34.08 mmol) in dichloromethane (100 mL) cooled to −78° C. was added boron tribromide (9.38 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided 9.2 g of 2′,4′,6′-trichlorobiphenyl-2-ol as a yellow solid. Treatment of 2′,4′,6′-trichloro-1,1′-biphenyl-2-ol (9.17 g, 33.52 mmol) with potassium carbonate (18.53 g, 134.1 mmol) and allyl bromide (4.46 g, 36.87 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-2′,4′,6′-trichloro-1,1′-biphenyl-2-ol. Treatment of 3-allyl-2′,4′,6′-trichloro-1,1′-biphenyl-2-ol. (10.35 g, 33.00 mmol) with 3-chloroperoxybenzoic acid (17.08 g, 99.00 mmol, 77%) followed by potassium carbonate (11.40 g, 82.51 mmol) generally according to the procedure described for Intermediate 9 afforded 10.4 g (95%) of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (10.38 g, 31.49 mmol) with p-toluenesulfonyl chloride (7.20 g, 37.79 mol) generally according to the procedure described for Intermediate 10 gave 10.5 g (68%) of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.38 g, 2.85 mmol) with sodium azide (0.74 g, 11.4 mmol) generally according to the procedure described for Intermediate 98 afforded 0.93 g, (92%) of (±)-2-(azidomethyl)-7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran. To a solution of (±)-2-(azidomethyl)-7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran in tetrahydrofuran (75 mL) was added polymer-supported triphenylphosphine (1.36 g, 5.24 mmol) and the reaction was allowed to stir at room temperature 12 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, 10% aqueous ammonium hydroxide in methanol:ethyl acetate 1:9) provided a colorless oil. The oil was re-dissolved in isopropanol (2 mL) and hydrogen chloride (6 mL, 1.0 M in diethyl ether) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to give 0.53 g (56%) of (±)-{[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp >225° C.

EXAMPLE 167 (±)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (1.01 g, 13%) following the general procedure of Example 154 as a white solid, hydrochloride salt from 1-bromo-4-chloro-2-methyl-benzene (5.0 g, 24.33 mmol) and (2-methoxyphenyl)boronic acid (4.8 g, 31.63 mmol). mp 175-177° C.

EXAMPLE 168 (±)-{[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.68 g, 31%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmol) and (5-chloro-2-methylphenyl)boronic acid (0.334 g, 1.96 mmol). mp 146-150° C.

EXAMPLE 169 (±)-{[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.68 g, 35%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmol) and (5-chloro-2-methyoxlphenyl)boronic acid (0.365 g, 1.96 mmol). mp 149-152° C.

EXAMPLE 170 (±)-[(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine

The title compound was prepared (0.770 g, 69%) following the general procedure of Example 154 as a light brown solid, hydrochloride salt from (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.0 g, 10.44 mmol) and pyridine-3-ylboronic acid (3.85 g, 31.31 mmol). mp 158-162° C.

EXAMPLE 171 (+)-{[7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.17 g, 78%) following the general procedure of Example 129 as a yellow solid, hydrochloride salt from (+)-benzyl {[7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.30 g, 0.832 mmol) and trimethylsilyl iodide (0.66 g, 3.33 mmol). [α]_(D) ²⁵=+27.2 (c 10.0 in methanol); mp 168-171° C.

EXAMPLE 172 (−)-{[7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.172 g, 78%) following the general procedure of Example 129 as a light yellow solid, hydrochloride salt from (+)-benzyl {[7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.33 g, 0.91 mmol) and trimethylsilyl iodide (0.73 g, 3.64 mmol). [α]_(D) ²⁵=−20.4 (c 10.0 in methanol); mp 168-171° C.

EXAMPLE 173 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-phenylamine

To a solution of (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.5 mmol) in toluene (20 mL) was added bromobenzene (0.23 g, 1.5 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.061 g, 0.075 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.125 g, 0.225 mmol), and sodium tert-butoxide (0.18 g, 1.875 mmol) and the reaction mixture was allowed to reflux 3 h. The solvent was removed in vacuo. The residue was washed with water (100 mL) and ethyl acetate (50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:10) afforded (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate with sodium azide (0.18 g, 2.78 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-N-phenyl-2,3-dihydro-1-benzofuran-7-amine. Treatment of the azide with polymer-supported triphenylphosphine (1.09 g, 4.17 mmol) generally according to the procedure described for Example 21 provided 0.042 g, (46%) of (±)-2-(aminomethyl)-N-phenyl-2,3-dihydro-1-benzofuran-7-amine as a white solid, fumarate salt. mp 216-218° C.

EXAMPLE 174 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-methylphenyl)amine

The title compound was prepared (0.171 g, 15%) following the general procedure of Example 173 as a white solid, fumarate salt from (+)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 4-bromotoluene (0.51 g, 3.0 mmol). mp 226-228° C.

EXAMPLE 175 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-chlorophenyl)amine

The title compound was prepared (0.158 g, 18%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mol) and 1-bromo-4-chlorobenzene (0.57 g, 3.0 mmol). mp 223-224° C.

EXAMPLE 176 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-methoxyphenyl)amine

The title compound was prepared (0.048 g, 5%) following the general procedure of Example 173 as a yellow solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-4-methoxybenzene (0.896 g, 3.0 mmol). mp 178-180° C.

EXAMPLE 177 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-[4-(trifluoromethyl)phenyl]amine

The title compound was prepared (0.227 g, 18%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-4-(trifluoromethyl)benzene (0.675 g, 3.0 mmol). mp 218-220° C.

EXAMPLE 178 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-fluorophenyl)amine

The title compound was prepared (0.066 g, 7%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-4-fluorobenzene (0.52 g, 3.0 mmol). mp 234-236° C.

EXAMPLE 179 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3,4-dichlorophenyl)amine

The title compound was prepared (0.171 g, 15%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-3,4-dichlorobenzene (0.68 g, 3.0 mmol). mp 229-231° C.

EXAMPLE 180 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(2,4-dimethylphenyl)amine

The title compound was prepared (0.234 g, 24%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-2,4-dimethylbenzene (0.55 g, 3.0 mmol). mp 232-234° C.

EXAMPLE 181 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3,4-dimethylphenyl)amine

The title compound was prepared (0.115 g, 12%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-3,4-dimethylbenzene (0.55 g, 3.0 mmol). mp 232-234° C.

EXAMPLE 182 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-methylphenyl)amine

The title compound was prepared (0.16 g, 17%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 3-bromotoluene (0.51 g, 3.0 mmol). mp 217-218° C.

EXAMPLE 183 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-fluorophenyl)amine

The title compound was prepared (0.266 g, 28%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 4-bromo-3-fluorobenzene (0.525 g, 3.0 mmol). mp 219-221° C.

EXAMPLE 184 (±)-N-2-(aminomethyl)-N-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-7-amine

The title compound was prepared (0.195 g, 18%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-3-(trifluoromethyl)benzene (0.675 g, 3.0 mmol). mp 212-214° C.

EXAMPLE 185 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-methoxy-3-methylphenyl)amine

The title compound was prepared (0.03 g, 3%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 5-bromo-2-methoxytoluene (0.603 g, 3.0 mmol). mp 205-207° C.

EXAMPLE 186 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3,5-difluorophenyl)amine

The title compound was prepared (0.185 g, 19%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-3,5-difluorobenzene (0.57 g, 3.0 mmol). mp 229-231° C.

EXAMPLE 187 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-trifluoromethoxy)phenyl]amine

The title compound was prepared (0.144 g, 11%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-3-(trifluoromethoxy)benzene (0.723 g, 3.0 mmol). mp 199-201° C.

EXAMPLE 188 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-chloro-4-methylphenyl)amine

The title compound was prepare (0.282 g, 27%) d following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 4-bromo-2-chlorotoluene (0.63 g, 3.0 mmol). mp 225-227° C.

EXAMPLE 189 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3,5-dichlorophenyl)amine

The title compound was prepared (0.065 g, 6%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-3,5-dichlorophenylbenzene (0.678 g, 3.0 mmol). mp >250° C.

EXAMPLE 190 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-chlorophenyl)amine

The title compound was prepared (0.284 g, 28%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 4-bromo-3-chlorophenylbenzene (0.57 g, 3.0 mmol). mp 220-222° C.

EXAMPLE 191 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(4-chloro-3-methylphenyl)amine

The title compound was prepared (0.298 g, 28%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 5-bromo-3-chlorotoluene (0.629 g, 3.0 mmol). mp 225-227° C.

EXAMPLE 192 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3,5-dimethylphenyl)amine

The title compound was prepared (0.178 g, 18%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-3,5-dimethylbenzene (0.57 g, 3.0 mmol). mp >250° C.

EXAMPLE 193 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(3-chloro-4-fluorophenyl)amine

The title compound was prepared (0.167 g, 16%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-3-chloro-4-fluorobenzene (0.63 g, 3.0 mmol). mp 244-245° C.

EXAMPLE 194 (±)-N-[2-(aminomethyl)-2,3-dihydro-1-benzofuran-7-yl]-N-(2-fluorophenyl)amine

The title compound was prepared (0.070 g, 7%) following the general procedure of Example 173 as a white solid, fumarate salt from (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) and 1-bromo-2-fluorobenzene (0.52 g, 3.0 mmol). mp 203-205° C.

EXAMPLE 195 (±)-{[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.16 g, 88%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate 1.0 g, 2.5 mmol) and (2-methoxyphenyl)boronic acid (0.57 g, 3.7 mmol). mp 219-220° C.

EXAMPLE 196 (±)-{[5-fluoro-7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.136 g, 46%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate 0.40 g, 1.0 mmol) and (3-fluorophenyl)boronic acid (0.22 g, 1.50 mmol). mp 193-194° C.

EXAMPLE 197 (±)-{[5-fluoro-7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.175 g, 64%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate 0.4 g, 0.996 mmol) and (3-methoxyphenyl)boronic acid (0.23 g, 1.51 mmol). mp 172-175° C.

EXAMPLE 198 (±)-{[5-fluoro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.178 g, 68%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.996 mmol) and (3-methylphenyl)boronic acid (0.21 g, 1.51 mmol). mp 228-230° C.

EXAMPLE 199 (±)-{[5-fluoro-7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.160 g, 54%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.0 mmol) and (4-fluorophenyl)boronic acid (0.22 g, 1.50 mmol). mp 241-243° C.

EXAMPLE 200 (±)-{[5-fluoro-7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.173 g, 55%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.0 mmol) and (4-chlorophenyl)boronic acid (0.25 g, 1.50 mmol). mp 221-225° C.

EXAMPLE 201 (±)-{[5-fluoro-7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.211 g, 72%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.996 mmol) and (4-methylphenyl)boronic acid (0.20 g, 1.51 mmol). mp 180-183° C.

EXAMPLE 202 (±)-{[5-fluoro-7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.209 g, 68%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate 0.4 g, 0.996 mmol) and (4-methoxyphenyl)boronic acid (0.23 g, 1.51 mmol). mp 175-176° C.

EXAMPLE 203 (±)-[(5-fluoro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine

The title compound was prepared (0.233 g, 82%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.996 mmol) and 3-thienylboronic acid (0.19 g, 1.51 mmol). mp 272-274° C.

EXAMPLE 204 (±)-{[5-fluoro-7-(3-furyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.076 g, 33%) following the general procedure of Example 154 as a yellow solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.996 mmol) and 3-furylboronic acid (0.18 g, 1.51 mmol). mp 236-239° C.

EXAMPLE 205 (±)-[(5-fluoro-7-pyridin-2-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine

The title compound was prepared (0.060 g, 11%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.60 g, 1.49 mmol) and 2-(tri-tert-butylstannyl)pyridine (2.6 g, 7.0 mmol 85%). mp 196-198° C.

EXAMPLE 206 (±)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine

The title compound was prepared (0.072 g, 13%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.60 g, 1.49 mmol) and pyridin-3-ylboronic acid (0.55 g, 4.5 mmol). mp 173-175° C.

EXAMPLE 207 (−)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine

Treatment of 0.58 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (6 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.181 g (15%) of (−)-{[5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−16.74 (c 10.0 in methanol); mp 88-90° C.

EXAMPLE 208 (+)-{[5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.59 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (6 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave 0.181 g (15%) of (+)-{[5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+13.71 (c 10.0 in methanol); mp 86-89° C.

EXAMPLE 209 (±)-[(5-fluoro-7-pyridin-4-yl-2,3-dihydro-O-benzofuran-2-yl)methyl]amine

The title compound was prepared (0.029 g, 5%) following the general procedure of Example 154 as a off-white solid, fumarate salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 0.996 mmol) and pyridin-4-ylboronic acid (0.18 g, 1.5 mmol). mp 170-171° C.

EXAMPLE 210 (±)-[(5-fluoro-7-pyrimidin-5-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine

The title compound was prepared (0.010 g, 5%) following the general procedure of Example 154 as a white solid, fumarate salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 0.996 mmol) and pyrimidin-5-ylboronic acid (0.52 g, 4.0 mmol). mp 65° C. (dec).

EXAMPLE 211 (±)-{[7-(2,3-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.076 g, 35%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 0.996 mmol) and 2,3-dichlorophenylboronic acid (0.856 g, 4.5 mmol). mp 185-187° C.

EXAMPLE 212 (±)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.143 g, 40%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.25 mmol) and 2,3-dimethoxyphenylboronic acid (0.68 g, 3.0 mmol). mp 90-93° C.

EXAMPLE 213 (−)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.60 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (1.10 g, 5.6 mmol) generally according to the procedure described for Example 129 gave 0.341 g (73%) of (−)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−54.27 (c 10.0 in methanol); mp 173-175° C.

EXAMPLE 214 (+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.80 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (1.44 g, 7.2 mmol) generally according to the procedure described for Example 129 gave 0.253 g (41%) of (+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+53.38 (c 10.0 in methanol); mp 166-167° C.

EXAMPLE 215 (±)-{[7-(2,4-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.163 g, 52%) following the general procedure of Example 154 as a off-white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 0.996 mmol) and 2,4-difluorophenylboronic acid (0.708 g, 4.5 mmol). mp 218-220° C.

EXAMPLE 216 (±)-{[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.049 g, 14%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 0.996 mmol) and 2,4-dichlorophenylboronic acid (0.856 g, 4.5 mmol). mp 107-109° C.

EXAMPLE 217 (−)-{[5-fluoro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.50 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (1.12 g, 4.40 mmol) generally according to the procedure described for Example 129 gave 0.234 g (60%) of (−)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−2.07 (c 10.0 in methanol); mp 175-178° C.

EXAMPLE 218 (+)-{[5-fluoro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.50 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (1.12 g, 4.40 mmol) generally according to the procedure described for Example 129 gave 0.220 g (56%) of (+)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [ ]_(D) ²⁵=+1.80 (c 10.0 in methanol); mp 203-205° C.

EXAMPLE 219 (±)-{[7-(2,4-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.068 g, 20%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 0.996 mmol) and 2,4-dimethoxyphenylboronic acid (0.819 g, 4.5 mmol). mp 141-143° C.

EXAMPLE 220 (±)-{[7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.068 g, 20%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 0.996 mmol) and 2,5-difluorophenylboronic acid (0.473 g, 3.0 mmol). mp 203-205° C.

EXAMPLE 221 (±)-{[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.098 g, 28%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 0.996 mmol) and 2,5-dichlorophenylboronic acid (0.57 g, 3.0 mmol). mp 165-166° C.

EXAMPLE 222 (±)-{[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.026 g, 9%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 0.996 mmol) and 2,5-dimethylphenylboronic acid (0.45 g, 3.0 mmol). mp 153-155° C.

EXAMPLE 223 (±)-{[7-(2,5-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.064 g, 19%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 0.996 mmol) and 2,5-dimethoxyphenylboronic acid (0.54 g, 3.0 mmol). mp 120-122° C.

EXAMPLE 224 (±)-{[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.083 g, 26%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.41 g, 1.0 mmol) (5-methoxy-2-methylphenyl)boronic acid (0.5 g, 3.0 mmol). mp 233-235° C.

EXAMPLE 225 (±)-{[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.017 g, 5%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.0 mmol) (2-methoxy-5-methylphenyl)boronic acid (0.51 g, 3.0 mmol). mp 110-111° C.

EXAMPLE 226 (±)-{[7-(2,6-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.140 g, 9%) following the general procedure of Example 166 as a white solid, hydrochloride salt from (2,6-difluorophenyl)boronic acid (4.0 g, 23.5 mmol) and (2-bromo-1,3-difluorobenzene (3.1 g, 15.7 mmol). mp 235-237° C.

EXAMPLE 227 (±)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.109 g, 3%) following the general procedure of Example 166 as a white solid, hydrochloride salt from (2,6-dimethylphenyl)boronic acid (4.0 g, 23.0 mmol) and 2-bromo-1,3-dimethylbenzene (2.9 g, 15.6 mmol). mp 241-243° C.

EXAMPLE 228 (+)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.50 g of fraction 1 obtained from the chiral HPLC separation of (±)-[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate with sodium azide (0.38 g, 58.5 mmol) generally according to the procedure described for Example 1 gave 0.28 g (80%) of (+)-2-(azidomethyl)-7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran as a colorless oil. Treatment of the azide with triphenyl phosphine (0.74 g, 2.82 mmol) generally according to the procedure described for Example 154 afforded a white solid, hydrochloride salt; [α]_(D) ²⁵=+10.83 (c 10.0 in methanol); mp 192-194° C.

EXAMPLE 229 (−)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.50 g of fraction 2 obtained from the chiral HPLC separation of (±)-[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate with sodium azide (0.38 g, 58.5 mmol) generally according to the procedure described for Example 1 gave 0.22 g (63%) of (−)-2-(azidomethyl)-7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran as a colorless oil. Treatment of the azide with triphenyl phosphine (0.58 g, 2.22 mmol) generally according to the procedure described for Example 154 afforded a white solid, hydrochloride salt; [α]_(D) ²⁵=−6.6 (c 10.0 in methanol); mp 180-183° C.

EXAMPLE 230 (±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.21 g, 5%) following the general procedure of Example 166 as a white solid, hydrochloride salt from (5-fluoro-2-methoxyphenyl)boronic acid (3.0 g, 17.6 mmol) and 2-bromo-1,3-dichlorobenzene (2.65 g, 12.0 mmol). mp 204-205° C.

EXAMPLE 231 (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclopropanamine

The title compound was prepared (0.035 g, 30%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.30 mmol) and cyclopropylamine (0.17 g, 3.0 mmol). mp 112-113° C.

EXAMPLE 232 (±)-1-cyclopropyl-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methanamine

The title compound was prepared (0.066 g, 54%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.30 mmol) and (aminomethyl)cyclopropane (0.21 g, 3.0 mmol). mp 130-133° C.

EXAMPLE 233 (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclobutanamine

The title compound was prepared (0.074 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.30 mmol) and cyclobutylamine (0.21 g, 3.0 mmol). mp 128-130° C.

EXAMPLE 234 (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}ethanamine

The title compound was prepared (0.068 g, 56%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.32 mmol) and ethylamine (0.138 g, 3.2 mmol). mp 138.140° C.

EXAMPLE 235 (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}propan-1-amine

The title compound was prepared (0.092 g, 84%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.13 g, 0.28 mmol) and propylamine (0.165 g, 2.80 mmol). mp >250° C.

EXAMPLE 236 (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}propan-2-amine

The title compound was prepared (0.065 g, 66%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.3 mmol) and isopropylamine (0.18 g, 3.0 mmol). mp 134-135° C.

EXAMPLE 237 (±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}dimethylamine

The title compound was prepared (0.069 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.3 mmol) and dimethylamine (0.14 g, 3.0 mmol). mp 199-201° C.

EXAMPLE 238 (±)-1-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}piperidine

The title compound was prepared (0.074 g, 69%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.12 g, 0.26 mmol) and piperidine (0.22 g, 2.6 mmol). mp 184-186° C.

EXAMPLE 239 (±)-1-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}morpholine

The title compound was prepared (0.069 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.30 mmol) and morpholine (0.26 g, 3.0 mmol). mp 196-199° C.

EXAMPLE 240 (±)-1-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}pyrrolidine

The title compound was prepared (0.069 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.13 g, 0.28 mmol) and pyrrolidine (0.20 g, 2.8 mmol). mp 65-67° C.

EXAMPLE 241 (±)-{[5-chloro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.017 g, 39%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and (2-fluorophenyl)boronic acid (0.6 g, 4.3 mmol). mp 235-237° C.

EXAMPLE 242 (±)-{[5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.017 g, 10%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.1 g, 2.42 mmol) and (2-methoxyphenyl)boronic acid (1.55 g, 9.68 mmol). mp 240-242° C.

EXAMPLE 243 (±)-{[5-chloro-7-(3-furyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.017 g, 9%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 3-furylboronic acid (0.54 g, 4.82 mmol). mp >250° C.

EXAMPLE 244 (±)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.131 g, 56%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 2,3-difluorophenylboronic acid (0.76 g, 4.81 mmol). mp 216-218° C.

EXAMPLE 245 (−)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.66 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (15 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 2 gave a crude salt. The salt was washed with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with saturated aqueous sodium chloride (100 mL), dried (sodium sulfate), and the solvent was removed in vacuo to provide a colorless oil. The oil was re-dissolved in isopropanol (3 mL) and hydrogen chloride (1.0 N in diethyl ether, 10.0 mL) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.391 g (76%) of (−)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−13.8 (c 10.0 in methanol); mp 225-227° C.

EXAMPLE 246 (+)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.63 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (15 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.387 g (66%) of (+)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+10.6 (c 10.0 in methanol); mp 225-227° C.

EXAMPLE 247 (±)-{[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.160 g, 55%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 2,3-dichlorophenylboronic acid (0.92 g, 4.81 mmol). mp 245-246° C.

EXAMPLE 248 (±)-{[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.072 g, 31%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 2,3-dimethylphenylboronic acid (0.70 g, 4.81 mmol). mp 223-225° C.

EXAMPLE 249 (±)-{[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.137 g, 47%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 2,3-dimethoxyphenylboronic acid (0.88 g, 4.81 mmol). mp 120-122° C.

EXAMPLE 250 (±)-{[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.134 g, 57%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 2,4-difluorophenylboronic acid (0.76 g, 4.81 mmol). mp 216-218° C.

EXAMPLE 251 (±)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.10 g, 42%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 2,4-dichlorophenylboronic acid (0.92 g, 4.81 mmol). mp 202-204° C.

EXAMPLE 252 (−)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.67 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (15 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.465 g (88%) of (−)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−8.5 (c 10.0 in methanol); mp 237-239° C.

EXAMPLE 253 (+)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.42 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (15 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.275 g (83%) of (±)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt; [α]_(D) ²⁵=+10.1 (c 10.0 in methanol); mp 240-242° C.

EXAMPLE 254 (±)-{[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.075 g, 45%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 2,4-dimethoxyphenylboronic acid (0.88 g, 4.81 mmol). mp 220-222° C.

EXAMPLE 255 (±)-{[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.118 g, 42%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 2,5-difluorophenylboronic acid (0.76 g, 4.81 mmol). mp 242-244° C.

EXAMPLE 256 (±)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.137 g, 52%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 2,5-dichlorophenylboronic acid (0.92 g, 4.81 mmol). mp 160-162° C.

EXAMPLE 257 (±)-{[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.159 g, 56%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and (5-chloro-2-methoxyphenyl)boronic acid (0.90 g, 4.81 mmol). mp 174-176° C.

EXAMPLE 258 (±)-{[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.121 g, 44%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 3,4-difluorophenylboronic acid (0.76 g, 4.81 mmol). mp >250° C.

EXAMPLE 259 (±)-{[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.068 g, 47%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 3-chloro-4-fluorophenylboronic acid (0.84 g, 4.81 mmol). mp 214-243° C.

EXAMPLE 260 (±)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.246 g, 53%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.505 g, 1.21 mmol) and 2,6-dimethylphenylboronic acid (2.8 g, 18.66 mmol). mp 173-175° C.

EXAMPLE 261 (−)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.67 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (15 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 provided 0.226 g (44%) of (−)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−16.9 (c 10.0 in methanol); mp 200-202° C.

EXAMPLE 262 (+)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.66 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (15 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 afforded 0.339 g (67%) of (+)-{[5-chloro-7-(2,6-dimethylphenyl) 2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+14.9 (c 10.0 in methanol); mp 204-206° C.

EXAMPLE 263 (±)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.072 g, 8%) following the general procedure of Example 166 as a white solid, hydrochloride salt from (5-chloro-2-methoxyphenyl)boronic acid (5.0 g, 26.88 mmol) and 2-bromo-1,3-dichlorobenzene (12.14 g, 53.76 mmol). mp 234-236° C.

EXAMPLE 264 (+)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.80 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (1.46 g, 7.20 mmol) generally according to the procedure described for Example 158 afforded 0.341 g (56%) of (+)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+33.61 (c 10.0 in methanol); mp >250° C.

EXAMPLE 265 (−)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.60 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (1.09 g, 5.60 mmol) generally according to the procedure described for Example 158 gave 0.253 g (55%) of (−)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−31.76 (c 10.0 in methanol); mp >250° C.

EXAMPLE 266 (±)-{[(5-chloro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine

The title compound was prepared (0.162 g, 45%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.20 mmol) and pyridin-3-ylboronic acid (0.50 g, 3.86 mmol). mp >250° C.

EXAMPLE 267 (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclopropanamine

The title compound was prepared (0.056 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and cyclopropylamine (0.39 g, 6.77 mmol). mp 214-216° C.

EXAMPLE 268 (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}(cyclopropylmethyl)amine

The title compound was prepared (0.058 g, 45%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and (aminomethyl)cyclopropane (0.50 g, 6.77 mmol). mp 203-205° C.

EXAMPLE 269 (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclobutanamine

The title compound was prepared (0.027 g, 21%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and cyclobutylamine (0.49 g, 6.77 mmol). mp 203-205° C.

EXAMPLE 270 No Compound EXAMPLE 271 (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}ethanamine

The title compound was prepared (0.079 g, 66%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and ethylamine (0.14 g, 3.38 mmol). mp 230-232° C.

EXAMPLE 272 (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}propan-2-amine

The title compound was prepared (0.064 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and isopropylamine (0.40 g, 6.76 mmol). mp 213-215° C.

EXAMPLE 273 No Compound EXAMPLE 274 (±)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}dimethylamine

The title compound was prepared (0.068 g, 57%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and dimethylamine (0.18 g, 6.76 mmol). mp 220-222° C.

EXAMPLE 275 (±)-1-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}piperidine

The title compound was prepared (0.095 g, 72%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and piperidine (0.58 g, 6.76 mmol). mp >235° C.

EXAMPLE 276 (±)-4-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}morpholine

The title compound was prepared (0.09 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and morpholine (0.58 g, 6.76 mmol). mp 228-230° C.

EXAMPLE 277 (±)-4-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}thiomorpholine

The title compound was prepared (0.55 g, 39%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and thiomorpholine (0.72 g, 6.76 mmol). mp 224-226° C.

EXAMPLE 278 (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}propan-1-amine

The title compound was prepared (0.094 g, 76%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and propylamine (0.40 g, 6.76 mmol) mp 200-202° C.

EXAMPLE 279 (±)-1-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}piperazine

The title compound was prepared (0.118 g, 81%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and piperazine (0.58 g, 6.76 mmol). mp 190-192° C.

EXAMPLE 280 (±)-1-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}pyrrolidine

The title compound was prepared (0.094 g, 73%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and pyrrolidine (0.48 g, 6.76 mmol). mp 245-247° C.

EXAMPLE 281 (±)-{[(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine

Treatment of 2-bromo-4-methylphenol (19.09 g, 102 mmol) with potassium carbonate (56.0 g, 400 mmol) and allyl bromide (15.96 g, 130 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-methylphenol. Treatment of 2-allyl-6-bromo-4-methylphenol (5.21 g, 23.0 mmol) with 3-chloroperoxybenzoic acid (9.13 g, 34.50 mmol, 77%) followed by potassium carbonate (7.9 g, 57.5 mmol) generally according to the procedure described for Intermediate 9 afforded 2.14 g (43%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (+)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (2.41 g, 10.0 mmol) with p-toluenesulfonyl chloride (2.1 g, 11.0 mol) generally according to the procedure described for Intermediate 10 gave 3.31 g (84%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.25 g, 0.63 mmol) and phenylboronic acid (0.23 g, 1.89 mmol) generally according to the procedure described for Intermediate 154 afforded 0.23 g, (93%) of (±)-(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.15 g (97%) of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.297 g, 1.13 mmol) according to the procedure described in Example 21 afforded 0.106 g (61%) of (±)-[(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 227-228° C.

EXAMPLE 282 (±)-{[7-(2-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.111 g, 49%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.76 mmol) and 2-methylphenylboronic acid (0.32 g, 3.00 mmol). mp 260-263° C.

EXAMPLE 283 (±)-{[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.136 g, 46%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.00 mmol) and 2-fluorophenylboronic acid (0.42 g, 3.00 mmol). mp 232-234° C.

EXAMPLE 284 (±)-{[7-(2-methoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.136 g, 44%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.00 mmol) and 2-methoxyphenylboronic acid (0.46 g, 3.00 mmol). mp 194-195° C.

EXAMPLE 285 No Compound EXAMPLE 286 (±)-{[7-(2-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.135 g, 58%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.76 mmol) and 2-chlorophenylboronic acid (0.35 g, 2.28 mmol). mp 260-263° C.

EXAMPLE 287 (±)-({5-methyl-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)amine

The title compound was prepared (0.135 g, 58%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.31 g, 0.76 mmol) and 2-(trifluoromethyl)phenylboronic acid (0.36 g, 2.28 mmol). mp 211-213° C.

EXAMPLE 288 (±)-{[7-(3-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.028 g, 9%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.00 mmol) and 3-chlorophenylboronic acid (0.47 g, 3.00 mmol). mp 90-93° C.

EXAMPLE 289 (±)-{[7-(3-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.107 g, 37%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.00 mmol) and 3-methylphenylboronic acid (0.41 g, 3.00 mmol). mp 235-237° C.

EXAMPLE 290 (±)-{[7-(4-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.116 g, 38%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.00 mmol) and 4-methylphenylboronic acid (0.46 g, 3.00 mmol). mp 172-173° C.

EXAMPLE 291 (±)-{[7-(4-fluorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.112 g, 39%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.00 mmol) and 4-fluorophenylboronic acid (0.42 g, 3.00 mmol). mp 225-227° C.

EXAMPLE 292 (±)-{[7-(4-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.097 g, 31%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.00 mmol) and 4-chlorophenylboronic acid (0.47 g, 3.00 mmol). mp 250-252° C.

EXAMPLE 293 (±)-{[7-(4-methoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.116 g, 38%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.00 mmol) and 4-methoxyphenylboronic acid (0.49 g, 3.00 mmol). mp 207-209° C.

EXAMPLE 294 (±)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.164 g, 44%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,3-dimethoxyphenylboronic acid (0.69 g, 3.75 mmol). mp 97-99° C.

EXAMPLE 295 (−)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.59 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (1.08 g, 5.44 mmol) generally according to the procedure described for Example 158 gave 0.316 g (69%) of (−)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−73.6 (c 10.0 in methanol); mp 120-123° C.

EXAMPLE 296 (+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.52 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (0.956 g, 4.80 mmol) generally according to the procedure described for Example 158 afforded 0.127 g (32%) of (+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+74.51 (c 10.0 in methanol); mp 98-100° C.

EXAMPLE 297 (±)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.124 g, 29%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,4-dichlorophenylboronic acid (0.72 g, 3.8 mmol). mp 172-173° C.

EXAMPLE 298 (−)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.50 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (0.905 g, 4.52 mmol) generally according to the procedure described for Example 129 provided 0.275 g (71%) of (−)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−8.0 (c 10.0 in methanol); mp 173-176° C.

EXAMPLE 299 (+)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.48 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (0.868 g, 4.34 mmol) generally according to the procedure described for Example 129 afforded 0.254 g (68%) of (+)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+7.25 (c 10.0 in methanol); mp 173-176° C.

EXAMPLE 300 (±)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.121 g, 28%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,5-dichlorophenylboronic acid (0.72 g, 3.8 mmol). mp 155-156° C.

EXAMPLE 301 (±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.030 g, 11%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,6-dimethylphenylboronic acid (0.76 g, 4.00 mmol). mp 234-235° C.

EXAMPLE 302 (±)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.030 g, 21%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.56 g, 1.41 mmol) and 2,6-dichlorophenylboronic acid (2.17 g, 14.10 mmol). mp 193-195° C.

EXAMPLE 303 (−)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.72 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (1.28 g, 7.20 mmol) generally according to the procedure described for Example 158 gave 0.227 g (41%) of (−)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−28.9 (c 10.0 in methanol); mp 222-224° C.

EXAMPLE 304 (+)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.65 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (1.18 g, 6.00 mmol) generally according to the procedure described for Example 158 gave 0.259 g (51%) of (+)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride; [α]_(D) ²⁵=+33.82 (c 10.0 in methanol); salt. mp 222-224° C.

EXAMPLE 305 (±)-{[5-ethyl-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

To a solution of 4-ethylphenol (10.0 g, 82.0 mmol) in acetonitrile (250 mL) cooled to 0° C. was slowly added N-bromosuccinimide (16.0 g, 90 mmol) and the reaction mixture was allowed to stir at 0° C. for 1 h. The solvent was removed in vacuo and the reaction mixture was diluted with ice water (500 mL) and diethyl ether (500 mL). A solid precipitate was removed via filtration and the aqueous phase was separated and extracted with ethyl ether (2×200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) gave 8.35 g (51%). Treatment of 2-bromo-4-ethylphenol (8.35 g, 41.0 mmol) with potassium carbonate (14.3 g, 100 mmol) and allyl bromide (6.57 g, 130 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-ethylphenol. Treatment of 2-allyl-6-bromo-4-ethylphenol (5.18 g, 22.0 mmol) with 3-chloroperoxybenzoic acid (8.60 g, 33.0 mmol, 77%) followed by potassium carbonate (7.4 g, 55.0 mmol) generally according to the procedure described for Intermediate 9 afforded 3.94 g (70%) of (±)-(7-bromo-5-ethyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-ethyl-2,3-dihydro-1-benzofuran-2-yl)methanol (3.94 g, 15.0 mmol) with p-toluenesulfonyl chloride (3.5 g, 18.0 mol) generally according to the procedure described for Intermediate 10 gave 5.78 g (92%) of (±)-(7-bromo-5-ethyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-ethyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.73 mmol) and 2-methylphenylboronic acid (0.30 g, 2.19 mmol) generally according to the procedure described for Intermediate 35 afforded 0.30 g, (97%) of (±)-(5-ethyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.23 g, 3.55 mmol) generally according to the procedure described for Intermediate 98 afforded 0.16 g (77%) of (±)-2-(azidomethyl)-5-ethyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-ethyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.786 g, 0.869 mmol) according to the procedure described in Example 154 afforded 0.009 g (4%) of (±)-[(5-ethyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 198° C. (dec).

EXAMPLE 306 (±)-{[5-ethyl-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.174 g, 74%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-ethyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.3 g, 0.73 mmol) and 2-chlorophenylboronic acid (0.34 g, 2.19 mmol). mp 268-271° C.

EXAMPLE 307 (±)-{[5-isopropyl-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

To a solution of 4-isopropylphenol (13.38 g, 98.0 mmol) with N-bromosuccinimide (17.5 g, 98 mmol) generally according to the procedure described for Example 305 afforded 13.78 g (65%) of 2-bromo-4-isopropylphenol. Treatment of 2-bromo-4-isopropylphenol (13.74 g, 41.0 mmol) with potassium carbonate (22.0 g, 160 mmol) and allyl bromide (9.23 g, 76.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-isopropylphenol. Treatment of 2-allyl-6-bromo-4-isopropylphenol (6.85 g, 27.0 mmol) with 3-chloroperoxybenzoic acid (7.72 g, 27.0 mmol, 77%) followed by potassium carbonate (9.3 g, 67.5.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.12 g, (17%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (+)(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.12 g, 4.6 mmol) with p-toluenesulfonyl chloride (1.32 g, 6.9 mmol) generally according to the procedure described for Intermediate 10 gave 1.90 g (97%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.94 mmol) and 2-methylphenylboronic acid (0.38 g, 2.82 mmol) generally according to the procedure described for Intermediate 35 afforded 0.19 g, (46%) of (5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.141 g, 2.17 mmol) generally according to the procedure described for Intermediate 98 afforded 0.11 g (83%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.188 g, 0.716 mmol) according to the procedure described in Example 154 afforded 0.055 g (48%) of (±)-[(5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 221-222° C. (dec).

EXAMPLE 308 (±)-{[5-isopropyl-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.096 g, 30%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.94 mmol) and 2-chlorophenylboronic acid (0.44 g, 2.81 mmol). mp 257-260° C.

EXAMPLE 309 (±)-{[5-cyclopentyl-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

To a solution of 4-cyclopentylphenol (3.0 g, 18.0 mmol) in acetonitrile (30 mL) cooled to 0° C. was slowly added N-bromosuccinimide (3.29 g, 18 mmol) generally according to the procedure described for Example 309 afforded 3.75 g (84%) of 2-bromo-4-cyclopentylphenol Treatment of 2-bromo-4-cyclopentylphenol (3.75 g, 16.0 mmol) with potassium carbonate (5.4.0 g, 40 mmol) and allyl bromide (2.38 g, 20.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-cyclopentylphenol. Treatment of 2-allyl-6-bromo-4-cyclopentylphenol (3.0 g, 10.0 mmol) with 3-chloroperoxybenzoic acid (3.49 g, 12.0 mmol, 77%) followed by potassium carbonate (3.7 g, 25.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.68 g, (53%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.68 g, 4.6 mmol) with p-toluenesulfonyl chloride (0.96 g, 5.0 mmol) generally according to the procedure described for Intermediate 10 gave 1.78 g (70%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.1 mmol) and 2-methylphenylboronic acid (0.45 g, 3.3 mmol) generally according to the procedure described for Intermediate 35 afforded 0.51 g, (99%) of (5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.239 g, 3.67 mmol) generally according to the procedure described for Intermediate 98 afforded 0.16 g (65%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.24 g, 0.48 mmol) according to the procedure described in Example 154 afforded 0.126 g (50%) of (±)-[(5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 190-193° C. (dec).

EXAMPLE 310 (±)-{[5-cyclopentyl-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.171 g, 42%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.10 mmol) and 2-chlorophenylboronic acid (0.52 g, 3.30 mmol). mp 268-271° C.

EXAMPLE 311 (±)-2-(aminomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile

Treatment of 3-bromo-4-hydroxybenzonitrile (10.0 g, 50.0 mmol) with potassium carbonate (27.9 g, 200 mmol) and allyl bromide (7.96 g, 66.0 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromo-4-hydroxybenzonitrile. Treatment of 3-allyl-5-bromo-4-hydroxybenzonitrile (4.63 g, 19.0 mmol) with 3-chloroperoxybenzoic acid (6.2 g, 35.93 mmol, 77%) followed by potassium carbonate (6.56 g, 47.5 mmol) generally according to the procedure described for Intermediate 9 afforded 1.30 g (426) of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile (1.3 g, 5.0 mmol) with p-toluenesulfonyl chloride (1.02 g, 5.4 mol) generally according to the procedure described for Intermediate 10 gave 1.5 g (72%) of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.73 mmol) and 2-methylphenylboronic acid (0.3 g, 2.20 mmol) generally according to the procedure described for Intermediate 35 afforded 0.33 g, (99%) of (±)-[5-cyano-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.26 g, 4.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (74%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of the azide with polymer-supported triphenylphosphine (0.24 g, 0.67 mmol) according to the procedure described in Example 154 afforded 0.118 g (53%) of (±)-2-(aminomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile as a white solid, hydrochloride salt. mp 127-129° C.

EXAMPLE 312 (±)-2-(aminomethyl)-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile

The title compound was prepared (0.27 g, 57%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.60 g, 1.50 mmol) and 2-chlorophenylboronic acid (0.69 g, 4.50 mmol). mp 173-175° C.

EXAMPLE 313 (±)-{[5-(trifluoromethyl)-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

To a solution of 4-(trifluoromethyl)phenol (5.0 g, 30.86 mmol) in carbon tetrachloride (100 mL) cooled to 0° C. was added dropwise over 4 hours bromine (4.94 g, 30.86 mmol) in carbon tetrachloride (25 mL) and the reaction mixture was allowed to stir at 0° C. for 24 h. The reaction mixture was washed with 10% aqueous sodium bisulfite (100 mL) and dichloromethane (300 mL). The aqueous phase was separated and extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) gave 4.69 g (63%). Treatment of 2-bromo-4-(trifluoromethyl)phenol (4.69 g, 19.5 mmol) with sodium hydride (0.86 g, 21.0 mmol 60%) and allyl bromide (2.5 g, 21.0 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-(trifluoromethyl)phenol. Treatment of 2-allyl-6-bromo-4-(trifluoromethyl)phenol (3.66 g, 13.0 mmol) with 3-chloroperoxybenzoic acid (5.84 g, 26.0 mmol, 77%) followed by potassium carbonate (2.5 g, 19.5 mmol) generally according to the procedure described for Intermediate 9 afforded 3.50 g (91%) of (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-(trifluoromethyl-2,3-dihydro-1-benzofuran-2-yl)methanol (3.5 g, 11.78 mmol) with p-toluenesulfonyl chloride (3.6 g, 17.67 mol) generally according to the procedure described for Intermediate 10 gave 5.0 g (94%) of (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2-fluorophenylboronic acid (0.26 g, 2.13 mmol) generally according to the procedure described for Intermediate 35 afforded 0.11 g, (81%) of (±)-[7-(2-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.21 g, 3.2 mmol) generally according to the procedure described for Intermediate 98 afforded 0.16 g (88%) of (±)-2-(azidomethyl)-5-(trifluoromethyl)-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-(trifluoromethyl)-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.20 g, 0.76 mmol) according to the procedure described in Example 154 afforded 0.053 g (24%) of (+)-[(5-(trifluoromethyl)-7-(phenyl)-1-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp >250° C.

EXAMPLE 314 (±)-{[5-(trifluoromethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.148 g, 65%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2-methylphenylboronic acid (0.36 g, 2.64 mmol). mp 253-255° C.

EXAMPLE 315 (±)-{[5-(trifluoromethyl)-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.27 g, 57%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.325 g, 0.72 mmol) and 2-chlorophenylboronic acid (0.169 g, 2.88 mmol). mp 192-194° C.

EXAMPLE 316 (±)-{[5-(trifluoromethyl)-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.21 g, 87%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2-methoxyphenylboronic acid (0.40 g, 2.64 mmol). mp 203-205° C.

EXAMPLE 317 (±)-{[5-(trifluoromethyl)-7-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.088 g, 33%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2-(trifluoromethyl)phenylboronic acid (0.50 g, 2.64 mmol). mp 195-197° C.

EXAMPLE 318 (±)-{[5-(trifluoromethyl)-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.092 g, 40%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 3-methylphenylboronic acid (0.50 g, 2.64 mmol). mp >250° C.

EXAMPLE 319 (±)-{[5-(trifluoromethyl)-7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.068 g, 30%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 3-fluorophenylboronic acid (0.50 g, 2.64 mmol). mp >250° C.

EXAMPLE 320 (±)-{[5-(trifluoromethyl)-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.102 g, 42%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 3-chlorophenylboronic acid (0.41 g, 2.64 mmol). mp 238-240° C.

EXAMPLE 321 (±)-{[5-(trifluoromethyl)-7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.125 g, 52%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 3-methoxyphenylboronic acid (0.40 g, 2.64 mmol). mp 202-204° C.

EXAMPLE 322 (±)-{[5-(trifluoromethyl)-7-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.038 g, 14%) following the general procedure of Example 154 as a off-white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 3-(trifluoromethyl)phenylboronic acid (0.50 g, 2.64 mmol). mp 225-227° C.

EXAMPLE 323 (±)-{[5-(trifluoromethyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.102 g, 46%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 4-methylphenylboronic acid (0.36 g, 2.64 mmol). mp 248-250° C.

EXAMPLE 324 (±)-{[5-(trifluoromethyl)-7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.119 g, 52%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 4-fluorophenylboronic acid (0.37 g, 2.64 mmol). mp >250° C.

EXAMPLE 325 (±)-{[5-(trifluoromethyl)-7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.036 g, 15%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 4-chlorophenylboronic acid (0.42 g, 2.64 mmol). mp >250° C.

EXAMPLE 326 (±)-{[5-(trifluoromethyl)-7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.130 g, 54%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 4-methoxyphenylboronic acid (0.40 g, 2.64 mmol). mp 248-250° C.

EXAMPLE 327 (±)-{[5-(trifluoromethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.105 g, 40%) following the general procedure of Example 154 as white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 4-(trifluoromethyl)phenylboronic acid (0.50 g, 2.64 mmol). mp >250° C.

EXAMPLE 328 (±)-{[7-(2,3-dimethylphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.124 g, 58%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2,3-dimethylphenylboronic acid (0.40 g, 2.64 mmol). mp 198-200° C.

EXAMPLE 329 (±)-{[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.059 g, 25%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2,3-difluorophenylboronic acid (0.30 g, 1.90 mmol). mp. 217-218° C.

EXAMPLE 330 (±)-{[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.045 g, 17%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2,3-dichlorophenylboronic acid (0.50 g, 2.64 mmol). mp 152-155° C.

EXAMPLE 331 (±)-{[7-(2,3-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.080 g, 31%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2,3-dimethoxyphenylboronic acid (0.48 g, 2.64 mmol). mp 178-180° C.

EXAMPLE 332 (±)-{[7-(2,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.163 g, 67%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2,4-difluorophenylboronic acid (0.30 g, 1.90 mmol). mp 237-239° C.

EXAMPLE 333 (±)-{[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.098 g, 38%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2,4-dimethoxyphenylboronic acid (0.48 g, 2.64 mmol). mp 210-212° C.

EXAMPLE 334 (±)-{[7-(3,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.063 g, 26%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 3,4-difluorophenylboronic acid (0.42 g, 2.64 mmol). mp 237-239° C.

EXAMPLE 335 (±)-{[7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.044 g, 19%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 3-chloro-4-fluorophenylboronic acid (0.465 g, 2.64 mmol). mp >250° C.

EXAMPLE 336 (±)-{[7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.063 g, 26%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2,5-difluorophenylboronic acid (0.42 g, 2.64 mmol). mp >250° C.

EXAMPLE 337 (±)-{[7-(2,5-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.128 g, 48%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2,5-dichlorophenylboronic acid (0.503 g, 2.64 mmol). mp 203-205° C.

EXAMPLE 338 (±)-{[7-(2,6-dimethylphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.012 g, 4%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 2,6-dimethylphenylboronic acid (0.40 g, 2.64 mmol). mp 198-200° C.

EXAMPLE 339 (±)-{[7-(4-butylphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.122 g, 48%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 4-butylphenylboronic acid (0.28 g, 1.57 mmol). mp 190-192° C.

EXAMPLE 340 (±)-4-[2-(aminomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-7-yl]benzonitrile

The title compound was prepared (0.102 g, 35%) following the general procedure of Example 154 as a white solid from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 4-cyanophenylboronic acid (0.23 g, 1.57 mmol). mp 238-239° C.

EXAMPLE 341 (±)-{[7-(3-furyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.053 g, 25%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66° mmol) and 3-furylphenylboronic acid (0.22 g, 1.96 mmol). mp >250° C.

EXAMPLE 342 (±)-{[7-thien-3-yl-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.164 g, 73%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and 3-thienylboronic acid (0.34 g, 2.64 mmol). mp >250° C.

EXAMPLE 343 (±)-{[7-pyridin-3-yl-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.081 g, 30%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.66 mmol) and pyridine-3-ylboronic acid (0.24 g, 1.95 mmol). mp 200-202° C.

EXAMPLE 344 (±)-[(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine

Treatment of 3-bromo-4-hydroxybiphenyl (15.7 g, 63.0 mmol) with potassium carbonate (34.84 g, 252.0 mmol) and allyl bromide (9.15 g, 75.63 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromobiphenyl-4-ol. Treatment of 3-allyl-5-bromobiphenyl-4-ol (17.8 g, 61.5 mmol) with 3-chloroperoxybenzoic acid (31.87 g, 184.67 mmol, 77%) followed by potassium carbonate (21.27 g, 153.89 mmol) generally according to the procedure described for Intermediate 9 afforded 15.8 g (84%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol (15.8 g, 51.77 mmol) with p-toluenesulfonyl chloride (14.79 g, 77.65 mmol) generally according to the procedure described for Intermediate 10 gave 18.8 g (79%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.26 mmol) and phenylboronic acid (0.59 g, 4.89 mmol) generally according to the procedure described for Intermediate 35 afforded 1.17 g, (78%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.342 g, 5.26 mmol) generally according to the procedure described for Intermediate 98 afforded 0.39 g (91%) of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.314 g, 1.21 mmol) according to the procedure described in Example 154 afforded 0.34 g (99%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp >250° C.

EXAMPLE 345 (±)-{[7-(2-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.157 g, 39%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.09 mmol) and 2-chlorophenylboronic acid (0.255 g, 1.63 mmol). mp >250° C.

EXAMPLE 346 (±)-{[7-(3-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.166 g, 41%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.09 mmol) and 3-chlorophenylboronic acid (0.255 g, 1.63 mmol). mp 240-242° C.

EXAMPLE 347 (±)-{[7-(4-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.092 g, 22%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.09 mmol) and 4-chlorophenylboronic acid (0.255 g, 1.63 mmol). mp 200-203° C.

EXAMPLE 348 (±)-{[7-(2-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.153 g, 39%) following the general procedure of Example 154 as a light yellow solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.09 mmol) and 2-fluorophenylboronic acid (0.228 g, 1.63 mmol). mp >250° C.

EXAMPLE 349 (±)-{[7-(3-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared following the general procedure of Example 154 as a light yellow solid, hydrochloride salt (0.107 g, 28%) from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.09 mmol) and 3-fluorophenylboronic acid (0.228 g, 1.63 mmol). mp >250° C.

EXAMPLE 350 (±)-{[7-(4-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.106 g, 27%) following the general procedure of Example 154 as a light yellow solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.09 mmol) and 4-fluorophenylboronic acid (0.228 g, 1.63 mmol). mp >250° C.

EXAMPLE 351 (±)-{[7-(2-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.148 g, 39%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.09 mmol) and 2-methylphenylboronic acid (0.222 g, 1.63 mmol). mp 225-227° C.

EXAMPLE 352 (±)-{[7-(3-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.080 g, 21%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.09 mmol) and 3-methylphenylboronic acid (0.222 g, 1.63 mmol). mp 246-249° C.

EXAMPLE 353 (±)-{[7-(4-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.094 g, 25%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.09 mmol) and 4-methylphenylboronic acid (0.222 g, 1.63 mmol). mp 159-162° C.

EXAMPLE 354 (±)-{[7-(2,4-difluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.157 g, 38%) following the general procedure of Example 154 as white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.09 mmol) and (2,4-difluorophenyl)boronic acid (0.258 g, 1.63 mmol). mp 159-162° C.

EXAMPLE 355 (±)-{[7-(2,5-dichlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.168 g, 38%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.09 mmol) and (2,5-dichlorophenyl)boronic acid (0.312 g, 1.63 mmol). mp 159-162° C.

EXAMPLE 356 (±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.121 g, 49%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.21 mmol) and 2-fluorophenylboronic acid (0.68 g, 4.84 mmol). mp >250° C.

EXAMPLE 357 (±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.121 g, 46%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.21 mmol) and 2-chlorophenylboronic acid (0.75 g, 4.84 mmol). mp 179-181° C.

EXAMPLE 358 (±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.118 g, 48%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.21 mmol) and 2-methylphenylboronic acid (0.66 g, 4.84 mmol). mp 187-189° C.

EXAMPLE 359 (±)-{[7-(2-methoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.181 g, 33%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.42 mmol) and 2-methoxyphenylboronic acid (1.55 g, 9.68 mmol). mp 190-192° C.

EXAMPLE 360 (±)-{[5-methoxy-7-(3-thienyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.110 g, 46%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.21 mmol) and 3-thienylboronic acid (0.62 g, 4.84 mmol). mp 230-232° C.

EXAMPLE 361 (±)-{[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.141 g, 54%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,3-difluorophenylboronic acid (0.76 g, 4.84 mmol). mp 224-226° C.

EXAMPLE 362 (±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.087 g, 30%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,3-dichlorophenylboronic acid (0.92 g, 4.84 mmol). mp 159-161° C.

EXAMPLE 363 (±)-{[7-(2,3-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.132 g, 52%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,3-dimethylphenylboronic acid (0.70 g, 4.84 mmol). mp 129-130° C.

EXAMPLE 364 (±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.164 g, 63%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,4-difluorophenylboronic acid (0.76 g, 4.84 mmol). mp 226-228° C.

EXAMPLE 365 (±)-{[7-(2,4-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.091 g, 32%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,4-dichlorophenylboronic acid (0.92 g, 4.84 mmol). mp 180-182° C.

EXAMPLE 366 (±)-{[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.148 g, 56%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,5-difluorophenylboronic acid (0.76 g, 4.84 mmol). mp 118-120° C.

EXAMPLE 367 (±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.048 g, 16%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,5-dichlorophenylboronic acid (0.92 g, 4.84 mmol). mp 140-142° C.

EXAMPLE 368 (+)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.50 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (14 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.297 g (75%) of (+)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+6.62 (c 10.0 in methanol); mp 148-150° C.

EXAMPLE 369 (−)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.135 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (3 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.047 g (44%) of (−)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−6.73 (c 10.0 in methanol); mp 148-150° C.

EXAMPLE 370 (±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.134 g, 53%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,5-dimethylphenylboronic acid (0.70 g, 4.84 mmol). mp 214-216° C.

EXAMPLE 371 (±)-{[7-(2,5-dimethoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.070 g, 24%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,5-dimethoxyphenylboronic acid (0.88 g, 4.84 mmol). mp 128-130° C.

EXAMPLE 372 (±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.169 g, 60%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 5-chloro-2-methoxyphenylboronic acid (0.90 g, 4.84 mmol). mp 172-174° C.

EXAMPLE 373 (±)-{[7-(3-chloro-4-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.178 g, 65%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 3-chloro-4-fluorophenylboronic acid (0.84 g, 4.84 mmol). mp 220-222° C.

EXAMPLE 374 (±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.170 g, 67%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-(7-bromo-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.26 mmol) and 2,6-dimethylphenylboronic acid (0.92 g, 4.84 mmol). mp 212-214° C.

EXAMPLE 375 (±)-{[7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 4-bromo-2-fluorophenol (25.0 g, 130.9 mmol) with potassium carbonate (72.35 g, 523.53 mmol) and allyl bromide (19.00 g, 157.06 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-4-bromo-6-fluorophenol. Treatment of 2-allyl-4-bromo-6-fluorophenol (25.6 g, 110.8 mmol) with 3-chloroperoxybenzoic acid (57.36 g, 332.38 mmol, 77%) followed by potassium carbonate (38.28 g, 277.0 mmol) generally according to the procedure described for Intermediate 9 afforded 19.1 g (70%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol (18.61 g, 75.3 mmol) with p-toluenesulfonyl chloride (17.22 g, 90.34 mmol) generally according to the procedure described for Intermediate 10 gave 22.6 g (75%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.25 mmol) and 2-methylphenylboronic acid (0.254 g, 1.87 mmol) generally according to the procedure described for Intermediate 35 afforded 0.282 g, (55%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (99%) of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphen yl)-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.30 g, 3.0 mmol) according to the procedure described in Example 154 afforded 0.038 g (22%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]amine as a white solid, hydrochloride salt. mp >250° C.

EXAMPLE 376 (±)-{[7-fluoro-5-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.026 g, 24%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 2-chlorophenylboronic acid (0.292 g, 1.89 mmol). mp >250° C.

EXAMPLE 377 (±)-{[7-fluoro-5-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.055 g, 38%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 2-fluorophenylboronic acid (0.292 g, 1.89 mmol). mp >250° C.

EXAMPLE 378 (±)-({7-fluoro-5-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)amine

The title compound was prepared (0.059 g, 38%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and [2-(trifluoromethyl)phenyl]boronic acid (0.355 g, 1.89 mmol). mp 189-194° C. (dec).

EXAMPLE 379 (±)-{[7-fluoro-5-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.050 g, 38%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 2-methoxyphenylboronic acid (0.284 g, 1.89 mmol). mp 203-207° C. (dec).

EXAMPLE 380 (±)-{[7-fluoro-5-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.057 g, 40%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 3-methylphenylboronic acid (0.254 g, 1.89 mmol). mp >250° C.

EXAMPLE 381 (±)-{[7-fluoro-5-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.071 g, 52%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 3-fluorophenylboronic acid (0.292 g, 1.89 mmol). mp >250° C.

EXAMPLE 382 (±)-{[7-fluoro-5-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.065 g, 44%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 3-chlorophenylboronic acid (0.292 g, 1.89 mmol). mp >250° C.

EXAMPLE 383 (±)-({7-fluoro-5-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)amine

The title compound was prepared (0.055 g, 37%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 3-(trifluoromethyl)phenylboronic acid (0.355 g, 1.89 mmol). mp >250° C.

EXAMPLE 384 (±)-{[7-fluoro-5-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.042 g, 32%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 3-methoxyphenylboronic acid (0.284 g, 1.89 mmol). mp >250° C.

EXAMPLE 385 (±)-{[7-fluoro-5-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.061 g, 50%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 4-methylphenylboronic acid (0.254 g, 1.89 mmol). mp >250° C.

EXAMPLE 386 (±)-{[7-fluoro-5-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.085 g, 55%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 4-chlorophenylboronic acid (0.292 g, 1.89 mmol). mp >250° C.

EXAMPLE 387 (±)-{[7-fluoro-5-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.060 g, 47%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 4-fluorophenylboronic acid (0.292 g, 1.89 mmol). mp >250° C.

EXAMPLE 388 (±)-({7-fluoro-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)amine

The title compound was prepared (0.041 g, 26%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (0.355 g, 1.89 mmol). mp >250° C.

EXAMPLE 389 (±)-{[7-fluoro-5-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

The title compound was prepared (0.66 g, 51%) following the general procedure of Example 154 as a white solid, hydrochloride salt from of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. (0.50 g, 1.25 mmol) and 4-methoxyphenylboronic acid (0.284 g, 1.89 mmol). mp >250° C.

EXAMPLE 390 (±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}ethanamine

To a solution of (±)-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl 4-methylbenzenesulfonate (0.2 g, 0.46 mmol) in dimethylsulfoxide (5 mL) was added ethylamine (0.20 g, 4.4 mmol) and the reaction mixture was allowed to stir at 60° C. for 12 h. The reaction was diluted with water (10 mL) and ethyl acetate (2×10 mL). The combined organic layers were washed with water (3×20 mL) and saturated aqueous sodium chloride (20 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give an oil. The oil was re-dissolved in isopropanol (0.5 mL) and hydrogen chloride (0.5 mL, 1.0 M in diethyl ether) was added. The resulting precipitate was filtered, washed (diethyl ether), to give 0.084 g (57%) of (±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}ethanamine as a white solid, hydrochloride salt. mp 195-197° C.

EXAMPLE 391 (±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclopropanamine

The title compound was prepared (0.057 g, 39%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl 4-methylbenzenesulfonate (0.2 g, 0.46 mmol) and cyclopropylamine (0.254 g, 4.40 mmol). mp 182-184° C.

EXAMPLE 392 (±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}cyclobutanamine

The title compound was prepared (0.077 g, 39%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl 4-methylbenzenesulfonate (0.2 g, 0.46 mmol) and cyclobutylamine (0.317 g, 4.40 mmol). mp 185-188° C.

EXAMPLE 393 (±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}propan-2-amine

The title compound was prepared (0.054 g, 35%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl 4-methylbenzenesulfonate (0.2 g, 0.46 mmol) and isopropylamine (0.258 g, 4.40 mmol). mp 182-184° C.

EXAMPLE 394 No Compound EXAMPLE 395 (±)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 1-bromo-2-methylbenzene (10.06 g, 58.84 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.16 mmol), and sodium carbonate (6.2 g, 58.84 mmol) generally according to the procedure described for Intermediate 37 provided 2.35 g (37%) of 6-fluoro-2′-methylbiphenyl-2-yl methyl ether. A solution of 6-fluoro-2′-methylbiphenyl-2-yl methyl ether (2.35 g, 10.86 mmol) in hydrogen bromide (40 mL, 30 wt. % in acetic acid) was heated to 55° C. for 12 h. The reaction mixture was concentrated under in vacuo and the crude residue diluted with ethyl acetate (200 mL). The organic layer was carefully extracted with saturated bicarbonate solution (3×200 mL) was dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Treatment of 6-fluoro-2′-methybiphenyl-2-ol (2.17 g, 10.84 mmol) with sodium hydride (0.65 g, 16.26 mmol, 60 wt. %) and allyl bromide (0.96 g, 16.26 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.77 g, 7.3 mmol) with 3-chloroperoxybenzoic acid (3.2 g, 10.96 mmol, 77%) followed by potassium carbonate (1.2 g, 8.76 mmol) generally according to the procedure described for Intermediate 9 afforded 1.5 g (80%) of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 2.17 g (90%) of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.23 g, 0.56 mmol) with sodium azide (0.23 g, 3.54 mmol) generally according to the procedure described for Intermediate 98 afforded 0.135 g, (86%) of (±)-2-(azidomethyl)-6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran (0.135 g, 0.4 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.30 g, 0.9 mmol) generally according to the procedure described for Example 154 provided 0.11 g (67%) of (±)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 216-218° C.

EXAMPLE 396 (+)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.66 g of fraction 1 obtained from the chiral HPLC separation of (+)-benzyl {[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (5 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.276 g (76%) of (+)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 216-218° C.

EXAMPLE 397 (−)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.66 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[(6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (5 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.192 g (52%) of (−)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 216-218° C.

EXAMPLE 398 (±)-{[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 1-bromo-2-chlorobenzene (5.63 g, 29.4 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol) generally according to the procedure described for Intermediate 37 afforded 2.0 g (29%) of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether with hydrogen bromide (50 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (0.34 g, 14.35 mmol) and allyl bromide (1.74 g, 14.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 to provide 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.2 g, 4.56 mmol) with m-chloroperoxybenzoic acid (2.36 g, 13.68 mmol, 77%) and potassium carbonate (1.575 g, 11.4 mmol) generally according to the procedure described for Intermediate 9 afforded 0.7 g (55%) of (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 0.9 g (82%) of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.15 mmol) with sodium azide (0.4 g, 6.15 mmol) generally according to the procedure described for Intermediate 98 afforded 0.35 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran (0.35 g, 1.15 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.60 g, 2.3 mmol) generally according to the procedure described for Example 154 provided 0.170 g (47%) of (±)-{[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 248-250° C.

EXAMPLE 399 (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 1-bromo-2-methylbenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (13.8 g, 80.6 mol) generally according to the procedure described for Intermediate 37 afforded 3.85 g (62%) of 6-chloro-2′-methylbiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (100 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded brown oil. The oil was reacted with sodium hydride (0.61 g, 25.38 mmol) and allyl bromide (3.07 g, 25.38 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol (4.38 g, 16.92 mmol) with m-chloroperoxybenzoic acid (4.38 g, 25.38 mmol, 77%) and potassium carbonate (2.81 g, 20.30 mmol) generally according to the procedure described for Intermediate 9 afforded 2.4 g (52%) of (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (2.4 g, 8.73 mmol) with p-toluenesulfonyl chloride (2.50 g, 13.1 mmol) generally according to the procedure described for Intermediate 10 gave 3.2 g (85%) of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) with sodium azide (0.35 g, 5.38 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.468 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.24 g, 0.936 mmol) generally according to the procedure described for Example 154 provided 0.028 g (18%) of (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 204-206° C.

EXAMPLE 400 (±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 1-bromo-2-chlorobenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl) boronic acid (15.6 g, 80.64 mol) generally according to the procedure described for Intermediate 37 afforded 5.0 g (73%) of 6-chloro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (60 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (1.05 g, 26.35 mmol) and allyl bromide (3.19 g, 26.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol (2.8 g, 10.03 mmol) with m-chloroperoxybenzoic acid (4.6 g, 15.0 mmol, 77%) and potassium carbonate (1.6 g, 12.0 mmol) generally according to the procedure described for Intermediate 9 afforded 2.2 g (74%) of (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.6 g, 5.42 mmol) with p-toluenesulfonyl chloride (1.55 g, 8.13 mmol) generally according to the procedure described for Intermediate 10 gave 2.1 g (86%) of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.44 mmol) with sodium azide (0.2 g, 3.08 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.43 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.3 g, 1.14 mmol) generally according to the procedure described for Example 154 provided 0.036 g (24%) of (±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 221-223° C.

EXAMPLE 401 (±)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.053 g, 72%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.1 g, 0.24 mmol) and methylamine (0.31 g, 10.0 mmol). mp 200-202° C.

EXAMPLE 402 (±)-{[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.12 g, 40%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 0.92 mmol) and methylamine (0.55 g, 17.7 mmol). mp 170-173° C.

EXAMPLE 403 (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.02 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.1 g, 0.23 mmol) and methylamine (0.24 g, 7.8 mmol). mp 158-160° C.

EXAMPLE 404 (±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.056 g, 73%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.1 g, 0.23 mmol) and methylamine (0.24 g, 7.8 mmol). mp 155-157° C.

EXAMPLE 405 No Compound EXAMPLE 406 (±)-[(N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.055 g, 24%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.20 g, 0.826 mmol) and 2-methylphenylboronic acid (0.168 g, 1.24 mmol). mp 166-169° C.

EXAMPLE 407 (−)-N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.325 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl methyl {[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (0.671 g, 3.3 mmol) generally according to the procedure described for Example 158 gave 0.193 g (80%) of (−)-N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−22.2 (c 10.0 in methanol); mp 182-185° C.

EXAMPLE 408 (+)-N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 0.32 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl methyl {[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (0.67 g, 3.3 mmol) generally according to the procedure described for Example 158 gave 0.192 g (80%) of (+)-N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+26.4 (c 10.0 in methanol); mp 182-185° C.

EXAMPLE 409 (±)-[(N-methyl-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.078 g, 40%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.20 g, 0.826 mmol) and 2-chlorophenylboronic acid (0.194 g, 1.24 mmol). mp 163-165° C.

EXAMPLE 410 (+)-N-methyl-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 2.71 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl methyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (5.32 g, 26.57 mmol) generally according to the procedure described for Example 158 gave 1.23 g (60%) of (+)-N-methyl-1-[7-(2-chlorolphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+13.2 (c 10.0 in methanol); mp 154-157° C.

EXAMPLE 411 (−)-N-methyl-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 3.01 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl methyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with trimethylsilyl iodide (5.91 g, 29.52 mmol) generally according to the procedure described for Example 158 gave 1.80 g (76%) of (+)-N-methyl-1-[7-(2-chlorolphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−13.2 (c 10.0 in methanol); mp 154-157° C.

EXAMPLE 412 (±)-[(N-methyl-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.147 g, 66%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.300 g, 0.753 mmol) and methylamine (0.92 g, 29.5 mmol). mp 148-150° C.

EXAMPLE 413 (±)-[(N-methyl-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.250 g, 76%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.501 g, 1.22 mmol) and methylamine (4.56 g, 150.0 mmol). mp 157-159° C.

EXAMPLE 414 (±)-[(N-methyl-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.059 g, 26%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-methylphenylboronic acid (0.169 g, 1.24 mmol). mp 157-159° C.

EXAMPLE 415 (±)-[(N-methyl-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.38 g, 53%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-fluorophenylboronic acid (0.173 g, 1.24 mmol). mp 160-163° C.

EXAMPLE 416 (±)-[(N-methyl-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.59 g, 53%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-chlorophenylboronic acid (0.194 g, 1.24 mmol). mp 177-178° C.

EXAMPLE 417 (±)-[(N-methyl-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.41 g, 49%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-methoxyphenylboronic acid (0.188 g, 1.24 mmol). mp 148-151° C.

EXAMPLE 418 (±)-[(N-methyl-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.071 g, 34%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-methylphenylboronic acid (0.168 g, 1.24 mmol). mp 210-213° C.

EXAMPLE 419 (±)-[(N-methyl-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.049 g, 21%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-fluorophenylboronic acid (0.173 g, 1.24 mmol). mp 209-211° C.

EXAMPLE 420 (±)-[(N-methyl-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.037 g, 16%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-chlorophenylboronic acid (0.193 g, 1.24 mmol). mp 227-230° C.

EXAMPLE 421 (±)-[(N-methyl-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.052 g, 23%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-methoxyphenylboronic acid (0.188 g, 1.24 mmol). mp 214-217° C.

EXAMPLE 422 (±)-[(N-methyl-1-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.046 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.23 mmol) and methylamine (0.072 g, 2.3 mmol). mp 197-199° C.

EXAMPLE 423 (±)-[(N-methyl-1-[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.137 g, 63%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.283 g, 0.64 mmol) and methylamine (0.199 g, 6.42 mmol). mp 163-166° C.

EXAMPLE 424 (±)-[(N-methyl-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.137 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.366 g, 0.88 mmol) and methylamine (0.273 g, 8.80 mmol). mp 156-160° C.

EXAMPLE 425 (±)-[(N-methyl-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.137 g, 47%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.125 g, 0.278 mmol) and methylamine (0.086 g, 2.78 mmol). mp 190-192° C.

EXAMPLE 426 (±)-[(N-methyl-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.272 g, 82%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.435 g, 0.987 mmol) and methylamine (0.306 g, 9.87 mmol). mp 185-188° C.

EXAMPLE 427 (±)-[(N-methyl-1-[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.091 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.091 g, 0.22 mmol) and methylamine (0.069 g, 2.22 mmol). mp 186-189° C.

EXAMPLE 428 (±)-[(N-methyl-1-[7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.027 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.060 g, 0.14 mmol) and methylamine (0.045 g, 1.4 mmol). mp 172-174° C.

EXAMPLE 429 (±)-[(N-methyl-1-[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.068 g, 83%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.120 g, 0.26 mmol) and methylamine (1.24 g, 40.0 mmol). mp 147-149° C.

EXAMPLE 430 (±)-[(N-methyl-1-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.058 g, 79%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.213 mmol) and methylamine (0.045 g, 2.1 mmol). mp 201-203° C.

EXAMPLE 431 (±)-[(N-methyl-1-[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.051 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.103 g, 0.24 mmol) and methylamine (0.074 g, 2.4 mmol). mp 178-182° C.

EXAMPLE 432 (±)-[(N-methyl-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.039 g, 63%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.084 g, 0.205 mmol) and methylamine (1.86 g, 60.0 mmol). mp >250° C.

EXAMPLE 433 (±)-[(N-methyl-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.351 g, 77%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.595 g, 1.324 mmol) and methylamine (1.86 g, 60.0 mmol). mp 190-192° C.

EXAMPLE 434 (−)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.607 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (1.09 g, 5.49 mmol) generally according to the procedure described for Example 158 gave 0.409 g (86%) of (−)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−11.6 (c 10.0 in methanol); mp 195-197° C.

EXAMPLE 435 (+)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.625 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (1.131 g, 5.65 mmol) generally according to the procedure described for Example 158 gave 0.369 g (76%) of (+)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine. [α]_(D) ²⁵=+11.2 (c 10.0 in methanol); mp 195-197° C.

EXAMPLE 436 (±)-N-methyl-1-(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine

The title compound was prepared (0.367 g, 70%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.730 g, 1.91 mmol) and methylamine (1.14 g, 36.7 mmol). mp 212-215° C.

EXAMPLE 437 (±)-[(N-methyl-1-[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.094 g, 84%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.23 mmol) and methylamine (0.072 g, 2.3 mmol); mp 166-168° C.

EXAMPLE 438 (±)-{[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.060 g, 40%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.48 mmol) and methylamine (0.149 g, 4.80 mmol). mp 140-141° C.

EXAMPLE 439 (±)-{[5-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.075 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.44 mmol) and methylamine (0.136 g, 4.40 mmol). mp 141-143.

EXAMPLE 440 (±)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.038 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.36 mmol) and methylamine (0.112 g, 3.60 mmol). mp 102-104° C.

EXAMPLE 441 (−)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.22 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (0.416 g, 2.08 mmol) generally according to the procedure described for Example 158 gave 0.125 g (79%) of (−)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−18.58 (c 10.0 in methanol); mp 123-124° C.

EXAMPLE 442 (+)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.28 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (0.528 g, 2.64 mmol) generally according to the procedure described for Example 158 gave 0.124 g (61%) of (+)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+14.25 (c 10.0 in methanol); mp 123-124° C.

EXAMPLE 443 (±)-{[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.075 g, 37%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.27 g, 0.6 mmol) and methylamine (0.198 g, 6.0 mmol). mp 175-176° C.

EXAMPLE 444 (±)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.103 g, 74%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.18 g, 0.39 mmol) and methylamine (0.139 g, 3.9 mmol). mp 85-89° C.

EXAMPLE 445 (±)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.041 g, 40%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.13 g, 0.278 mmol) and methylamine (0.086 g, 2.78 mmol). mp 146-148° C.

EXAMPLE 446 (−)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.48 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (0.834 g, 4.17 mmol) generally according to the procedure described for Example 158 gave 0.200 g (53%) of (−)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−8.87 (c 10.0 in methanol); mp 162-163° C.

EXAMPLE 447 (+)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.48 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (0.834 g, 4.17 mmol) generally according to the procedure described for Example 158 gave 0.200 g (53%) of (+)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+8.61 (c 10.0 in methanol); mp 161-163° C.

EXAMPLE 448 (±)-{[7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.73 g, 44%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.22 g, 0.51 mmol) and methylamine (0.155 g, 5.1 mmol). mp 185-187° C.

EXAMPLE 449 (±)-{[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.123 g, 80%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.43 mmol) and methylamine (0.133 g, 4.3 mmol). mp 166-168° C.

EXAMPLE 450 (+)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.53 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (0.92 g, 4.60 mmol) generally according to the procedure described for Example 158 gave 0.204 g (49%) of (+)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+14.00 (c 10.0 in methanol); mp 118-120° C.

EXAMPLE 451 (−)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.54 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (0.96 g, 4.80 mmol) generally according to the procedure described for Example 158 gave 0.275 g (65%) of (−)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−22.30 (c 10.0 in methanol); mp 110-112° C.

EXAMPLE 452 (±)-{[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.76 g, 48%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) and methylamine (0.152 g, 4.9 mmol). mp 186-188° C.

EXAMPLE 453 (±)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.148 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.3 g, 0.70 mmol) and methylamine (0.22 g, 7.0 mmol). mp 175-178° C.

EXAMPLE 454 (±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.081 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.43 mmol) and methylamine (0.133 g, 4.3 mmol). mp 196-198° C.

EXAMPLE 456 (±)-{[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.73 g, 50%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.40 mmol) and methylamine (0.124 g, 4.0 mmol). mp 173-174° C.

EXAMPLE 457 (±)-{[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.77 g, 48%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.45 mmol) and methylamine (0.139 g, 4.5 mmol). mp 197-199° C.

EXAMPLE 458 (±)-{[7-(5-chloro-2-methoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.62 g, 38%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(5-chloro-2-methoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.45 mmol) and methylamine (0.139 g, 4.5 mmol). mp 189-190° C.

EXAMPLE 459 (±)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine

The title compound was prepared (0.056 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.20 g, 0.50 mmol) and methylamine (0.155 g, 5.0 mmol). mp 255-257° C.

EXAMPLE 460 (±)-[(5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.037 g, 29%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.39 g, 0.88 mmol) and methylamine (0.271 g, 8.8 mmol). mp 100-102° C.

EXAMPLE 461 (±)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.155 g, 62%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.333 g, 0.74 mmol) and methylamine (0.231 g, 7.4 mmol). mp 229-231° C.

EXAMPLE 462 (±)-[(5-chloro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.037 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.142 g, 0.33 mmol) and methylamine (0.102 g, 3.3 mmol). mp 159-161° C.

EXAMPLE 463 (±)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.068 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.148 g, 0.329 mmol) and methylamine (0.102 g, 3.29 mmol). mp 177-179° C.

EXAMPLE 464 (±)-{[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.051 g, 40%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.165 g, 0.341 mmol) and methylamine (0.106 g, 3.41 mmol). mp 219-221° C.

EXAMPLE 465 (±)-{[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.054 g, 47%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.149 g, 0.33 mmol) and methylamine (0.102 g, 3.3 mmol). mp 148-150° C.

EXAMPLE 466 (±)-{[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.046 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.172 g, 0.36 mmol) and methylamine (0.112 g, 3.6 mmol). mp 105-107° C.

EXAMPLE 467 (±)-{[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.059 g, 48%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.162 g, 0.36 mmol) and methylamine (0.112 g, 3.6 mmol). mp 163-165° C.

EXAMPLE 468 (±)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.059 g, 57%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.135 g, 0.28 mmol) and methylamine (0.086 g, 2.8 mmol). mp 202-204° C.

EXAMPLE 469 (±)-{[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.052 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.099 g, 0.21 mmol) and methylamine (0.065 g, 2.1 mmol). mp 206-208° C.

EXAMPLE 470 (±)-{[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.090 g, 67%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.175 g, 0.39 mmol) and methylamine (0.120 g, 3.9 mmol). mp 189-191° C.

EXAMPLE 471 (±)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.027 g, 23%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.152 g, 0.31 mmol) and methylamine (0.086 g, 3.1 mmol). mp 185-187° C.

EXAMPLE 472 (±)-{[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.027 g, 21%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.165 g, 0.34 mmol) and methylamine (0.107 g, 3.4 mmol). mp 193-195° C.

EXAMPLE 473 (±)-{[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.09 g, 79%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.149 g, 0.33 mmol) and methylamine (0.102 g, 3.3 mmol). mp 235-237° C.

EXAMPLE 474 (±)-[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.032 g, 48%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.086 g, 0.18 mmol) and methylamine (0.057 g, 1.8 mmol). mp 202-204° C.

EXAMPLE 475 (±)-{[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.03 g, 28%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-fluorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.34 mmol) and methylamine (0.105 g, 3.4 mmol). mp 153-155° C.

EXAMPLE 476 (±)-{[7-(2-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.060 g, 28%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-chlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.22 g, 0.50 mmol) and methylamine (0.155 g, 5.0 mmol). mp 194-196° C.

EXAMPLE 477 (±)-{[7-(2-methoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.041 g, 32%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-methoxyphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.17 g, 0.40 mmol) and methylamine (0.124 g, 4.0 mmol). mp 165-166° C.

EXAMPLE 478 (±)-{[7-(3-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.075 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(3-methylphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.17 g, 0.42 mmol) and methylamine (0.129 g, 4.2 mmol). mp 165-167° C.

EXAMPLE 479 (±)-{[7-(3-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.016 g, 13%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(3-chlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.16 g, 0.37 mmol) and methylamine (0.115 g, 3.7 mmol). mp 181-182° C.

EXAMPLE 480 (±)-{[7-(4-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.049 g, 44%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(4-methylphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.37 mmol) and methylamine (0.114 g, 3.7 mmol). mp 184-185° C.

EXAMPLE 481 (±)-{[7-(4-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.026 g, 21%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(4-chlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.16 g, 0.37 mmol) and methylamine (0.115 g, 3.7 mmol). mp 210-213° C.

EXAMPLE 482 (±)-{[7-(4-fluorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.028 g, 25%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(4-fluorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.36 mmol) and methylamine (0.112 g, 3.6 mmol). mp 206-208° C.

EXAMPLE 483 (±)-{[7-(4-methoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.075 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (+)-[7-(4-methoxyphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.45 mmol) and methylamine (0.112 g, 4.5 mmol). mp 235-238° C.

EXAMPLE 484 (±)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.094 g, 44%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-dimethoxyphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.18 g, 0.40 mmol) and methylamine (0.123 g, 4.0 mmol). mp 85-89° C.

EXAMPLE 485 (±)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.029 g, 14%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-dichlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.26 g, 0.56 mmol) and methylamine (0.174 g, 5.6 mmol). mp 169-171° C.

EXAMPLE 486 (±)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.034 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dichlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.16 g, 0.34 mmol) and methylamine (0.107 g, 3.4 mmol). mp 158-160° C.

EXAMPLE 487 (+)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.51 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (0.88 g, 4.4 mmol) generally according to the procedure described for Example 158 gave 0.256 g (64%) of (+)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+14.0 (c 10.0 in methanol); mp 192-194° C.

EXAMPLE 488 (−)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.50 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (0.88 g, 4.4 mmol) generally according to the procedure described for Example 158 gave 0.132 g (33%) of (−)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−12.99 (c 10.0 in methanol); mp 192-194° C.

EXAMPLE 489 (±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.035 g, 46%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dimethylphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.10 g, 0.24 mmol) and methylamine (0.073 g, 2.4 mmol). mp 204-205° C.

EXAMPLE 490 (±)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.073 g, 78%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dichlorophenyl)

-   5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl     4-methylbenzenesulfonate (0.12 g, 0.26 mmol) and methylamine (0.080     g, 2.6 mmol). mp 192-195° C.

EXAMPLE 491 (±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.039 g, 51%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.102 g, 0.24 mmol) and methylamine (0.074 g, 2.4 mmol). mp 110-112° C.

EXAMPLE 492 (±)-{([7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.040 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.102 g, 0.23 mmol) and methylamine (0.071 g, 2.3 mmol). mp 185-186° C.

EXAMPLE 493 (±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.055 g, 54%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.135 g, 0.32 mmol) and methylamine (0.099 g, 3.2 mmol). mp 167-169° C.

EXAMPLE 494 (±)-{[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.017 g, 18%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.12 g, 0.27 mmol) and methylamine (0.082 g, 2.7 mmol). mp 148-150° C.

EXAMPLE 495 (±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.053 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.135 g, 0.28 mmol) and methylamine (0.087 g, 2.8 mmol). mp 178-180° C.

EXAMPLE 496 (±)-{[7-(2,3-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.064 g, 64%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,3-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.132 g, 0.30 mmol) and methylamine (0.093 g, 3.0 mmol). mp 177-179° C.

EXAMPLE 497 (±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.062 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.132 g, 0.29 mmol) and methylamine (0.092 g, 2.9 mmol). mp 179-181° C.

EXAMPLE 498 (±)-{[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.027 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.129 g, 0.29 mmol) and methylamine (0.090 g, 2.9 mmol). mp 163-165° C.

EXAMPLE 499 (±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.061 g, 56%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.139 g, 0.29 mmol) and methylamine (0.090 g, 2.9 mmol). mp 179-181° C.

EXAMPLE 500 (±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.064 g, 62%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.135 g, 0.31 mmol) and methylamine (0.096 g, 3.1 mmol). mp 202-204° C.

EXAMPLE 501 (±)-{[7-(2,5-dimethoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.032 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,5-dimethoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.152 g, 0.32 mmol) and methylamine (0.100 g, 3.2 mmol). mp 144-145° C.

EXAMPLE 502 (±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.067 g, 58%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.148 g, 0.31 mmol) and methylamine (0.097 g, 3.1 mmol). mp 169-171° C.

EXAMPLE 503 (±)-{[7-(3-chloro-4-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.052 g, 46%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-chloro-4-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.14 g, 0.31 mmol) and methylamine (0.097 g, 3.1 mmol). mp 197-199° C.

EXAMPLE 504 (±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.076 g, 57%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.175 g, 0.40 mmol) and methylamine (0.12 g, 4.0 mmol). mp 170-172° C.

EXAMPLE 505 (±)-{[7-(2-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.066 g, 84%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.20 mmol) and methylamine (0.30 g, 9.8 mmol). mp 192-194° C.

EXAMPLE 506 (±)-{[7-(3-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.055 g, 69%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.20 mmol) and methylamine (0.30 g, 9.8 mmol). mp 211-214° C.

EXAMPLE 507 (±)-{[7-(4-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.056 g, 71%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.20 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.

EXAMPLE 508 (±)-{[7-(2-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.065 g, 83%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 204-206° C.

EXAMPLE 509 (±)-{[7-(3-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.058 g, 74%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.

EXAMPLE 510 (±)-{[7-(4-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.040 g, 51%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.

EXAMPLE 511 (±)-{[7-(2-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.055 g, 70%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 232-235° C.

EXAMPLE 512 (±)-{[7-(3-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.055 g, 70%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 230-234° C.

EXAMPLE 513 (±)-{[7-(4-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.051 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.213 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.

EXAMPLE 514 (±)-{[7-(2-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.060 g, 76%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 140-143° C.

EXAMPLE 515 (±)-{[7-(3-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.053 g, 67%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 206-209° C.

EXAMPLE 516 (±)-{[7-(4-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.081 g, 99%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.

EXAMPLE 517 (±)-{[7-(2,4-difluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.047 g, 59%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,4-difluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}-4-methylbenzenesulfonate (0.10 g, 0.20 mmol) and methylamine (0.30 g, 9.8 mmol). mp 188-191° C.

EXAMPLE 518 (±)-{[N-methyl-1-[7-phenyl-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.031 g, 67%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-phenyl-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.060 g, 0.13 mmol) and methylamine (0.12 g, 3.9 mmol). mp 189-190° C.

EXAMPLE 519 (±)-N-methyl-1-[7-(3-methylphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.026 g, 67%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(3-methylphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.050 g, 0.1 mmol) and methylamine (0.12 g, 3.9 mmol). mp 228-230° C.

EXAMPLE 520 (±)-N-methyl-1-[7-(3-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.026 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(3-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.055 g, 0.18 mmol) and methylamine (0.12 g, 3.9 mmol). mp 238-240° C.

EXAMPLE 521 (±)-N-methyl-1-[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.015 g, 19%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.12 g, 3.9 mmol). mp 123-125° C.

EXAMPLE 522 (±)-N-methyl-1-[7-(3,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.035 g, 48%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(3,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.093 g, 0.19 mmol) and methylamine (0.12 g, 3.9 m-mol). mp 235-237° C.

EXAMPLE 523 (±)-N-methyl-1-[7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.045 g, 58%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.12 g, 3.9 mmol). mp 138-140° C.

EXAMPLE 524 (±)-N-methyl-1-[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-2-benzofuran-2-yl]methanamine

The title compound was prepared (0.039 g, 49%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.10 g, 0.19 mmol) and methylamine (0.12 g, 3.9 mmol). mp 238-240° C.

EXAMPLE 525 (±)-{[7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.014 g, 19%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.19 mmol) and methylamine (0.12 g, 3.9 mmol). mp 229-230° C.

EXAMPLE 526 (±)-N-methyl-1-[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.048 g, 76%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.080 g, 0.16 mmol) and methylamine (0.12 g, 3.9 mmol). mp 234-236° C.

EXAMPLE 527 (±)-{[7-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.033 g, 58%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.070 g, 0.12 mmol) and methylamine (0.12 g, 3.9 mmol). mp 205-207° C.

EXAMPLE 528 (±)-{[7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.075 g, 75%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.141 g, 0.32 mmol) and methylamine (0.20 g, 6.4 mmol). mp 212-217° C. (dec).

EXAMPLE 529 (±)-{[7-fluoro-5-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.068 g, 47%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.199 g, 0.46 mmol) and methylamine (0.28 g, 9.2 mmol). mp 217-222° C. (dec).

EXAMPLE 530 (±)-{[7-fluoro-5-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.132 g, 92%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.20 g, 0.48 mmol) and methylamine (0.30 g, 9.6 mmol). mp >250° C. (dec).

EXAMPLE 531 (±)-{7-fluoro-5-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine

The title compound was prepared (0.02 g, 18%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[{7-fluoro-5-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (0.21 g, 0.45 mmol) and methylamine (0.28 g, 9.0 mmol). mp 196-200° C. (dec).

EXAMPLE 532 (±)-{7-fluoro-5-[2-methoxyphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine

The title compound was prepared (0.13 g, 92%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[{7-fluoro-5-[2-methoxyphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (0.18 g, 0.42 mmol) and methylamine (0.26 g, 8.4 mmol). mp 223-226° C. (dec).

EXAMPLE 533 (±)-{7-fluoro-5-[3-methylphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine

The title compound was prepared (0.14 g, 99%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[{7-fluoro-5-[3-methylphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (0.20 g, 0.48 mmol) and methylamine (0.30 g, 9.6 mmol). mp 245-250° C.

EXAMPLE 534 (±)-{7-fluoro-5-[3-chlorophenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine

The title compound was prepared (0.11 g, 81%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[{7-fluoro-5-[3-chlorophenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) and methylamine (0.30 g, 9.6 mmol). mp 225-232° C.

EXAMPLE 535 (±)-{[7-fluoro-5-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.12 g, 88%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.45 mmol) and methylamine (0.28 g, 9.1 mmol). mp >250° C.

EXAMPLE 536 (±)-{7-fluoro-5-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine

The title compound was prepared (0.034 g, 23%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[{7-fluoro-5-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (0.19 g, 0.42 mmol) and methylamine (0.26 g, 8.5 mmol). mp 215-219° C.

EXAMPLE 537 (±)-{7-fluoro-5-[3-methoxyphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine

The title compound was prepared (0.13 g, 99%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[{7-fluoro-5-[3-methoxyphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (0.18 g, 0.42 mmol) and methylamine (0.26 g, 8.3 mmol). mp 214-217° C.

EXAMPLE 538 (±)-{7-fluoro-5-[4-methylphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine

The title compound was prepared (0.11 g, 88%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[{7-fluoro-5-[4-methylphenyl]-2,3-dihydro-1-benzofuran-2-yl)}methyl 4-methylbenzenesulfonate (0.17 g, 0.41 mmol) and methylamine (0.26 g, 8.3 mmol). mp >250° C.

EXAMPLE 539 (±)-{7-fluoro-5-[4-chlorophenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine

The title compound was prepared (0.14 g, 91%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[{7-fluoro-5-[4-chlorophenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.

EXAMPLE 540 (±)-{[7-fluoro-5-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.12 g, 96%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.18 g, 0.43 mmol) and methylamine (0.27 g, 8.6 mmol). mp >250° C.

EXAMPLE 541 (±)-{7-fluoro-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine

The title compound was prepared (0.14 g, 87%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[{7-fluoro-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (0.21 g, 0.45 mmol) and methylamine (0.28 g, 9.0 mmol). mp >250° C.

EXAMPLE 542 (±)-{7-fluoro-5-[4-methoxyphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)methylamine

The title compound was prepared (0.12 g, 92%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[{7-fluoro-5-[4-methoxyphenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (0.18 g, 0.42 mmol) and methylamine (0.26 g, 8.4 mmol). mp >250° C.

EXAMPLE 543 (+){[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.71 g of fraction 1 obtained from the chiral HPLC separation of (±)-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate with methylamine (0.47 g, 15.0 mmol) generally according to the procedure described for Example 390 gave 0.42 g (76%) of (+)-{[(7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+7.89 (c 10.0 in methanol); mp 140-142° C.

EXAMPLE 544 (−){[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.79 g of fraction 2 obtained from the chiral HPLC separation of (±)-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate with methylamine (0.52 g, 16.9 mmol) generally according to the procedure described for Example 390 gave 0.39 g (64%) of (−)-{[(7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−9.02 (c 10.0 in methanol); mp 140-142° C.

EXAMPLE 545 (R)-[7-(2-chloro-phenyl)-5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl]-methyl-amine

Treatment of (R)-2-bromomethyl-7-(2-chloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran (0.55 g, 1.6 mmol) generally according to the procedure described for Example 390 gave 0.36 g (77%) of (R)-[7-(2-chloro-phenyl)-5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl]-methyl-amine as a white foam, hydrochloride salt. [α]_(D) ²⁵=+11.57 (c 7.43 in methanol); Anal. calcd. for C₁₆H₁₅ClFNOHCl: C, 58.55; H, 4.91; N, 4.27. Found: C, 56.86; H, 5.27; N, 3.91.

EXAMPLE 546 (R)-[7-(2,6-dichloro-phenyl)-5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl]ethylamine

Treatment of (R)-2-bromomethyl-7-(2,6-dichloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran (0.42 g, 1.1 mmol) generally according to the procedure described for Example 390 afforded 0.28 g (74%) of (R)-[7-(2,6-dichloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran-2-ylmethyl]ethylamine as a white foam, hydrochloride salt. MS ES [M+H]⁺ 340.1; [α]_(D) ⁵=−7.12 (c 7.86 in methanol); Anal. calcd. for C₁₇H₁₆Cl₂FNOHCl: C, 54.21; H, 4.55; N, 3.72. Found: C, 51.85; H, 4.88; N, 3.50.

EXAMPLE 547 (R)-[7-(2,6-dichloro-phenyl)-5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl]dimethylamine

Treatment of (R)-2-bromomethyl-7-(2,6-dichloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran (0.41 g, 1.1 mmol) and N,N-dimethylamine (2.0 M in tetrahydrofuran, 5.4 ml) generally according to the procedure described for Example 390 afforded 0.29 g (80%) of (R)-[7-(2,6-dichloro-phenyl)-5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl]-dimethyl-amine as a white solid, hydrochloride salt. mp 156-158° C.; [α]_(D) ²⁵=−21.04 (c 7.71 in methanol); Anal. calcd. for C₁₇H₁₆Cl₂FNOHCl: C, 54.21; H, 4.55; N, 3.72. Found: C, 53.98; H, 4.62; N, 3.56.

EXAMPLE 548 {[(2R)-7-(5-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of (R)-2-azidomethyl-7-(5-chloro-2-methyl-phenyl)-5-fluoro-2,3-dihydro-benzofuran (0.40 g, 1.2 mmol) generally according to the procedure described for Example 21 gave {[(2R)-7-(5-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 148-150° C.; [α]_(D) ²⁵=+1.45 (c 8.29 in methanol); Anal. calcd. for C₁₆H₁₅ClFNOHCl: C, 58.55; H, 4.91; N, 4.27. Found: C, 58.55; H, 4.78; N, 3.88.

EXAMPLE 549 {[(2R)-7-(4-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}anine

Treatment of (R)-2-azidomethyl-7-(4-chloro-2-methyl-phenyl)-5-fluoro-2,3-dihydrobenzo-furan (0.40 g, 1.2 mmol) generally according to the procedure described for Example 21 provided 0.29 g (80%) of {[(2R)-7-(4-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 183-185° C.; [α]_(D) ²⁵=+7.22 (c 9.14 in methanol); Anal. calcd. for C₁₆H₁₅ClFNOHCl: C, 58.55; H, 4.91; N, 4.27. Found: C, 58.55; H, 4.87; N, 4.52.

EXAMPLE 550 (−)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 0.95 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate with hydrogen bromide (20 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.38 g (57%) of (−)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−21.12 (c 10.0 in methanol); mp 228-230° C.

EXAMPLE 551 (+)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine

Treatment of 1.3 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate trimethylsilyl iodide (2.33 g, 11.6 mmol) generally according to the procedure described for Example 158 gave 0.78 g (77%) of (+)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. [α]_(D) ²⁵=16.46 (c 10.0 in methanol); mp 217-220° C.

EXAMPLE 552 (±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine

To a solution of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (0.5 g, 1.69 mmol) in toluene (10 mL) was added triphenylphosphine (0.66 g, 2.54 mmol), diethyl azodicarboxylate (0.44 g, 2.54 mmol), and 2-hydroxy-2-methylpropanenitrile (0.21 g, 2.53 mmol) and the reaction mixture was allowed to stir at room temperature for 48 h. The solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9-3:7) provided 0.22 g (43%) of (±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]propanenitrile. To a solution of the nitrile in tetrahydrofuran (10 mL) was added borane-tetrahydrofuran (8 mL) and the reaction mixture was heated to reflux for 3 h. The reaction mixture was quenched with 1.0 N aqueous hydrogen chloride (100 mL) and then neutralized with 1.0 N aqueous sodium hydroxide (100 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash column chromatography (silica, 10% ammonium hydroxide in methanol:dichloromethane 1:9) provided 0.1 g (19%) of (±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine as a white solid, hydrochloride salt. mp 211-213° C.

EXAMPLE 553 (±)-{2-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine

Treatment of (±)-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol (0.5 g, 1.9 mmol) with triphenylphosphine (1.23 g, 4.67 mmol), diethyl azodicarboxylate (0.82 g, 4.68 mmol), and 2-hydroxy-2-methylpropanenitrile (0.40 g, 4.68 mmol) generally according to the procedure described for Example 552 afforded 0.106 g (15%) of (±)-{2-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine as a white solid, hydrochloride salt. mp 212-213° C.

EXAMPLE 554 (±)-{2-[7-(2-methoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine

To a solution of (±)-[5-methoxy-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.25 g, 0.57 mmol) in dimethylsulfoxide (20 mL) was added sodium cyanide (0.07 g, 1.43 mmol) and the reaction mixture was allowed to stir at 50° C. for 1 h. The reaction was quenched by the addition of water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organics were washed with water (3×20 mL), saturated aqueous sodium chloride (20 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) gave (±)-[5-methoxy-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]acetonitrile as a colorless oil. The oil was dissolved in ethanol (30 mL), 28% aqueous ammonium hydroxide (20 mL), and treated with rhodium on alumina (0.1 g, 5 wt. %) generally according to procedure described for Example 1 to afford 0.025 g (13%) of (±)-{2-[5-methoxy-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine as a yellow solid, hydrochloride salt. mp 240-242° C.

EXAMPLE 555 (±)-{N-methyl-1-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

The title compound was prepared (0.424 g, 80%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.68 g, 1.4 mmol) and methylamine (3.1 g, 50.0 mmol). mp 169-172° C.

EXAMPLE 556 (+)-(N-methyl-1-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 1.48 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (2.48 g, 12.4 mmol) generally according to the procedure described for Example 158 provided 0.125 g (11%) of (+)-{N-methyl-1-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+7.8 (c 10.0 in methanol); mp 93-98° C.

EXAMPLE 557 (−)-{N-methyl-1-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine

Treatment of 1.41 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (2.36 g, 11.8 mmol) generally according to the procedure described for Example 158 gave 0.17 g (15%) of (−)-{N-methyl-1-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−6.2 (c 10.0 in methanol); mp 93-98° C.

EXAMPLE 558 (+)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.147 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (+)-[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.2 mmol) and methylamine (0.372 g, 12.0 mmol). [α]_(D) ²⁵=+1.6 (c 10.0 in methanol); mp 169-170° C.

EXAMPLE 559 (−)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

The title compound was prepared (0.298 g, 79%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (−)-[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.2 mmol) and methylamine (0.372 g, 12.0 mmol). [α]_(D) ²⁵=−3.0 (c 10.0 in methanol); mp 171-173° C.

EXAMPLE 560 (−)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.56 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with palladium on carbon (0.1 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.323 g (74%) of (−)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−5.9 (c 10.0 in methanol); mp 158-160° C.

EXAMPLE 561 (+)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.55 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with palladium on carbon (0.1 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.225 g (53%) of (+) {[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+4.51 (c 10.0 in methanol); mp 158-160° C.

EXAMPLE 562 (+)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.9 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-5-chloro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with hydrogen bromide (20 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.598 g (84%) of (+)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+14.27 (c 10.0 in methanol); mp 181-183° C.

EXAMPLE 563 (−)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.9 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,5-dichlorophenyl)-5-chloro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with hydrogen bromide (20 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.49 g (68%) of (−)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−7.8 (c 10.0 in methanol); mp 187-189° C.

EXAMPLE 564 (−)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.65 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with hydrogen bromide (15 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.395 g (78%) of (−)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=−8.4 (c 10.0 in methanol); mp 229-231° C.

EXAMPLE 565 (+)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.65 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with hydrogen bromide (15 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 245 gave 0.37 g (74%) of (+)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a white solid, hydrochloride salt. [α]_(D) ²⁵=+11.6 (c 10.0 in methanol); mp 229-231° C.

EXAMPLE 566 (+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.8 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (1.05 g, 5.2 mmol) generally according to the procedure described for Example 158 gave 0.16 g (28%) of (+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a light yellow foam, hydrochloride salt. [α]_(D) ²⁵=+38.89 (c 10.0 in methanol).

EXAMPLE 567 (−)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.67 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (1.05 g, 5.2 mmol) generally according to the procedure described for Example 158 gave 0.14 g (29%) of (−)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a light yellow foam, hydrochloride salt. [α]_(D) ²⁵=−38.0 (c 10.0 in methanol).

EXAMPLE 568 (−)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 0.88 g of fraction 1 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (1.55 g, 7.7 mmol) generally according to the procedure described for Example 158 gave 0.37 g (54%) of (−)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a light yellow foam, hydrochloride salt; [α]_(D) ²⁵=−26.4 (c 10.0 in methanol).

EXAMPLE 569 (+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine

Treatment of 1.4 g of fraction 2 obtained from the chiral HPLC separation of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate with trimethylsilyl iodide (2.53 g, 12.6 mmol) generally according to the procedure described for Example 158 gave 0.53 g (48%) of (+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine as a light yellow foam, hydrochloride salt; [α]_(D) ²⁵=25.2 (c 10.0 in methanol).

EXAMPLE 570 Alternative Synthesis of 2R-(−)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-2-aminomethylbenzofuran hydrochloride 1-Methoxy-4-flouro-2’,6’-dichlorobiphenyl

To a solution of NaOH (54 g, 1.35 mol) in water (400 mL) heated to 60° C. was added dimethoxyethane (400 mL), then dichlorobromobenzene (Aldrich, 60 g, 0.267 mol) and boronic acid (50 g, 0.294 mol). To the resulting stirred emulsion, solid Pd(PPh₃)₄ (9.5 g, 8.2 mmol) was added and washed down with 100 mL of DME. The greenish mixture was heated at reflux (ca. 80° C.) while stirred mechanically. The course of reaction was monitored by HPLC. After 2 hr, 9.0 g (0.053 mol) of additional boronic acid and 2.0 g (1.7 mmol) of the catalyst were added to the reaction mixture and the heating was continued for 16 hr longer. More boronic acid (5.8 g, 0.034 mol) and the catalyst (0.5 g, 0.4 mmol) were added at that point and the mixture was kept at reflux for 7 hr longer (23 hr was total reaction time).

The heating was stopped and 600 mL of heptane and 300 mL of water were added. The mixture was allowed to cool to room temperature and then was filtered through Celite. The layers were separated, the organic layer was washed with water, three times with brine, dried with MgSO₄ and filtered through a pad of Magnesol. The clear colorless solution was concentrated on a rotary evaporator to a colorless oil (weight 72 g). The oil was triturated with 120 mL of heptane which caused crystallization of a white solid. The mixture was left in a refrigerator overnight, the separated crystals were filtered and dried in air. Yield 51 g, 93% pure. The major impurity was determined to be the homo-coupling product 13. Additional recrystallization of the material from heptane gave crystals of 98% purity. Yield 45 g (62%) as white crystals.

1-Methoxy-2-bromo-4-fluoro-2′,6′-dichlorobiphenyl

To a magnetically stirred solution of the arene (38.0 g, 0.140 mol) in 190 mL of dioxane placed into a 500-mL round-bottom flask equipped with a temperature probe, cone, sulfuric acid (38 mL) was added slowly (exothermic mixing, temperature rose to 37° C., the solution turned yellow). To the warm solution (the arene would crystallize out of the mixture if it was allowed to cool down), solid NBS (26.7 g, 0.150 mol) was added in one portion (no exothermic heating was observed here). The resulting solution was heated in a mantle at 50° C. The reaction progress monitored by HPLC. After 18 hr, only trace amount of the starting arene was detected.

The reaction mixture was allowed to cool to room temperature (r.t.), then it was poured onto 400 g of ice (could use lesser amount as it did not melt completely). Heptane (100 mL) was added and the mixture was transferred to the separatory funnel. The aqueous layer was separated and extracted with additional portions of heptane (2×100 mL) (toluene could be used instead of heptane as the product started to crystallize; toluene was added to the organic solution to get the product back into the solution). Combined organic solutions were washed once with water (30 mL), then aq. Na₂S₂O₃ solution (to remove unreacted NBS, reaction with KI-starch indicator paper), and, finally, with 1 M aq. NaOH solution (2×30 mL) (upon NaOH treatment the mixture turned from yellow to dark-brown but all the color went into the aqueous phase). Light-yellow clear organic solution was dried with MgSO₄, filtered through a cotton plug and evaporated in vacuum (bath temp. 60° C.). The resulting yellow oil was re-dissolved in 55 mL of heptane.

The first batch of crystals (25.5 g) slowly separated from the heptane solution at r.t. and was filtered and dried in air. Purity 98% (HPLC @ 215 nm), white crystals. M.p. 67-69° C.

The second batch of the product (13.9 g) was isolated from the mother liquor by chilling it in a dry-ice-acetone bath, filtering off the precipitated solid and drying it in a vacuum desiccator over CaSO₄. Purity 97% (HPLC area % at 215 nm), white amorphous powder. M.p. 47-56° C.

Total yield 39.4 g (80%).

¹H NMR (300 MHz, CDCl₃) δ: 7.42 (m, J=8.1 Hz, 2H)¹⁰, 7.39 (dd, J=3.0, 7.7 Hz, 1H), 7.30 (dd, J=8.1 Hz, 1H), 6.86 (dd, J=3.0, 8.0 Hz, 1H), 3.56 (s, 3H). Protons at 7.42 and 7.30 ppm form a second-order A2B spin system with JAB=8.1 Hz (determined by NMR simulation).

EI MS, m/z.

2-[5-Fluoro-3-(2,6-dichlorophenyl)-2-methoxybenzyl]oxirane

Generation of the Grignard reagent. Aryl bromide (25.0 g, 71.4 mmol) was placed into a 500-mL flask equipped with a magnetic stirrer, nitrogen inlet, temperature probe and a rubber septum. The flask was purged excessively with nitrogen, then left under positive nitrogen pressure. Dry THF (100 mL) was transferred into the flask via a syringe. The solution was chilled in an ice bath to 2° C.

A solution of i-PrMgCl in THF (1.9 M, Aldrich, 39.5 mL, 75 mmol) was added slowly to the solution in the flask via a syringe (20 min addition time, the temperature was maintained between 2 and 6° C.). The resulting yellowish solution was left in the bath for 18 hr allowing it to reach room temperature. (The reaction is monitored by HPLC analysis of an aliquote quenched by water. Care should be taken not to introduce oxygen into the reaction flask while sampling the solution.)

Reaction with glycidyl tosylate. The solution of the Grignard reagent was chilled to −30° C. by placing the flask in a bath with partially frozen dichloroethane (M.p. −45° C.). CuCN (0.45 g, 5.0 mmol, 7 mol %; Aldrich) was added to the flask via syringe as a slurry in dry THF. The resulting mixture was stirred for 1 hr at −30° C., then (S)-(+)-glycidyl tosylate (15.5 g, 68 mmol, Aldrich) dissolved in 10 mL of dry THF was added to the solution (addition time 30 min, reaction mixture temperature was maintained between −22 and −29° C.). The reaction was left stirring at −31° C. for 2 hr, then the DCE bath was replaced with a partially frozen o-xylene bath (o-xylene M.p. −25° C.). Over the next 3 hr the temperature was allowed to reach −18° C. HPLC analysis of the quenched aliquot showed complete disappearance of glycidyl tosylate.

To the cold reaction mixture, 100 mL of aq. NH₄Cl solution (prepared by 1:1 dilution of the saturated solution with water) was added. The phases were separated. The aqueous layer was extracted with 50 mL of ME. Combined organic solutions were washed with 30 mL of brine.

Closure of the epoxide. To the solution of the intermediate hydroxytosylate was added aq. solution of NaOH prepared by mixing 20 mL of 10 M stock solution (200 mmol) with 30 mL of water. The resulting bi-phasic mixture was stirred rapidly with a magnetic stirrer so that the mixture was broken into fine emulsion. After 18 hr at room temp, (checked by HPLC) the mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with 100 mL of MTBE, combined organic solutions were washed with brine and dried with MgSO₄. After filtration through a paper filter, light-yellow solution was evaporated in vacuum to give a mixture the epoxide and des-bromo-arene as a light-yellow oil which solidified upon cooling to room temp. Weight 23.06 g. The mixture was used in the subsequent step without purification.

2S-3-[5-Fluoro-3-(2,6-dichlorophenyl)-2-methoxyphenyl]-1-N-phthalimidopropan-2-ol

The epoxide (22.6 g of the crude mixture from the previous step, ca. 67 mmol), phthalimide (10.3 g, 70 mmol) and its potassium salt (12.9 g, 70 mmol) were placed in a 250 round-bottom flask equipped with a magnetic stirrer, a nitrogen inlet, and a temperature probe. Dry DMF (100 mL) was added to the mixture. The reaction flask was briefly purged with nitrogen and then was being heated at 75° C. with stirring for 20 hr (the progress was monitored by HPLC). Once no starting epoxide was detected, the mixture was allowed to cool to room temp, and then mixed with 200 mL of ice-water slush. The product was extracted with MTBE (2×100 mL). The organic solution was washed with solution prepared from 2 parts of 1 M aq. NaOH, 3 parts brine, and 5 parts water (2×100 mL), then with brine until neutral pH (Note: The product may start crystallizing during the extractions and washes. In that case it was brought back into solution by adding THF to the mixture). The resulting organic solution was dried with MgSO₄, filtered through a paper filter and evaporated in vacuum. The product started to crystallize during the evaporation. The volume of the solvent was reduced to ca. 40 mL, then the residue was triturated with 200 mL of hexanes. The white solid was filtered, washed with hexanes and dried in air.

Yield 23.25 g (74% over 3 steps, based on the amount of glycidyl tosylate). M.p. 165-168° C.

¹H NMR (300 MHz, CDCl₃) δ: 7.86 (m, 2H), 7.72 (m, 2H), 7.43 (m, 1H), 7.41 (m, 1H), 7.27 (m, 1H), 7.08 (dd, J=3.0, 8.8 Hz, 1H), 6.79 (dd, J=3.0 Hz, 8.1 Hz, 1H), 4.23 (d⁵, J=3.3, 4.3, 5.7, 7.9, 8.5 Hz, 1H), 3.85 (dd, J=3.3, 14.1 Hz, 1H), 3.80 (dd, J=8.5, 14.1 Hz, 1H), 3.42 (s, 3H), 2.96 (dd, J=4.3, 13.9 Hz, 1H), 2.92 (dd, J=7.9, 13.9 Hz, 1H), 2.80 (d, J=5.7 Hz, 1H).

ES MS, m/z: 474 (N+H)⁺, Cl₂ isotope pattern. Analytical purity: 97% (HPLC area % at 215 nm).

2S-3-[5-Fluoro-3-(2,6-dichlorophenyl)-2-methoxyphenyl]-1-N-phthalimidopropan-2-yl methanesulfonate

In a 500 mL Erlenmeyer flask equipped with a magnetic stirrer, temperature probe and an addition funnel (suspended over the flask without attaching) was placed the product of the preceding step, 2S-3-[5-Fluoro-3-(2,6-dichlorophenyl)-2-methoxyphenyl]-1-N-phthalimidopropan-2-ol, (22.0 g, 46.4 mmol), CH₂Cl₂ (200 mL) and triethylamine (9.7 mL, 70 mmol). Into the addition funnel was placed CH₂Cl₂ (20 mL) and methanesulfonyl chloride (5.4 mL, 70 mL). The solution of MsCl was added dropwise (addition time 10 min) to the stirred solution in the flask (exothermic reaction, temp, rose to 32° C. by the end of addition). The reaction mixture was allowed to stir at room temp, for 2 hr (checked by HPLC). White solid separated from the solution over that time.

Water (100 mL) was added to the reaction mixture while stirring it rapidly. About 120 mL of DCM was distilled off on a rotary evaporator. The residue was triturated with 200 mL of hexanes. The solid was filtered and washed excessively with water and hexanes. The cake was dried on the filter for 1 hr then overnight in a vacuum desiccator oven.

Yield 25.2 g (98%) as a white fluffy crystals. M.p. >200° C. (decomp.)

¹H NMR (300 MHz, CDCl₃) δ: 7.86 (m, 2H), 7.72 (m, 2H), 7.43 (m, 2H), 7.29 (m, 1H), 7.09 (dd, J=3.1, 8.5 Hz, 1H), 6.82 (dd, J=3.1, 8.3 Hz, 1H), 5.28 (m, 1H), 4.09 (dd, J=8.6, 14.6 Hz, 1H), 3.90 (dd, J=3.3, 14.6 Hz, H), 3.45 (s, 3H), 3.18 (dd, J=5.4, 14.0 Hz, 1H), 3.09 (dd, J=7.8, 14.0 Hz, 1H), 2.65 (s, 3H). ¹³C NMR (100 MHz, dmso-J₆) δ: 167.6, 157.6 (d, J=242 Hz), 152.4 (d, J-2 Hz), 134.8, 134.4, 134.3 (d, J=16 Hz), 131.6, 131.4 (d, J=20 Hz), 131.4, 130.8, 128.3, 123.1, 118.7 (d, J=22 Hz), 116.7 (d, J=24 Hz), 78.5, 60.5, 40.8, 37.6, 33.2.

ES MS, m/z: 552 (M+H)⁺, Cl₂ isotope pattern. Analytical purity 99.6% (HPLC area % at 215 nm).

2R-7-(2,6-Dichlorophenyl)-5-fluoro-2,3-dihydro-2-(N-phthalimidomethyl)benzofuran

The product of the preceding step, 2S-3-[5-Fluoro-3-(2,6-dichlorophenyl)-2-methoxyphenyl]-1-N-phthalimidopropan-2-yl methanesulfonate, (22.1 g, 40.0 mmol) and dichloromethane (200 mL) were placed into a 500-mL flask equipped with a magnetic stirrer, a temperature probe, a nitrogen inlet and a 50-mL addition runnel. The flask and the addition runnel were purged briefly with nitrogen (just in case). The slurry in the flask was chilled in an ice bath to 4° C. A 1M solution of BBr₃ in CH₂Cl₂ (Aldrich, 42 mL, 42 mmol) was placed into the addition runnel and was added dropwise to the stirred contents of the flask (addition time 12 min, temp, drifted from 4 to 10° C.). The stirring was continued allowing the temperature of the reaction mixture to reach 16° C. over 2-hr period and then at room temp (19° C.) for 3 hr longer. The reaction progress was monitored by HPLC (1% of unreacted starting material remained, area % at 215 nm). 1M

The reaction mixture was quenched by slowly pouring it into the solution prepared from NaHCO₃ (11 g, 131 mmol) and 200 mL of water (the reaction went fairly slow, no exotherm was observed, no excessive foaming either). Precipitate formed initially in the organic layer but dissolved after ca. 20 min of rapid stirring. After 30 min of stirring, the layers were separated. Aqueous layer was extracted with dichloromethane (2×50 mL). Combined organic solutions were washed with 100 mL of water, then dried with MgSO₄ The drying agent was filtered off and washed with ethyl acetate. The volume of the filtrate was reduced to about 50 mL on rotary evaporator. The product separated as white or light-yellow solid. The slurry was triturated with 40 mL of a 50:50 hexanes-MTBE mixture, the solid was filtered, washed with the above mixture of solvents and dried on the filter.

Yield 14.4 g (82%) as a light-yellow solid. M.p. 222.5-224.5° C.

¹H NMR (400 MHz, dmso-J₆) δ: 7.85 (m, 4H), 7.53 (m, 2H), 7.41 (m, 1H), 7.19 (dd, J=2.7, 8.2 Hz, 1H), 6.86 (dd, 7=2.7, 9.3 Hz, 1H), 5.09 (m, 1H), 3.79 (m, 2H), 3.43 (dd, J=9.3, 16.6 Hz, 1H), 3.15 (dd, J=5.9, 16.6 Hz, 1H). ¹³C NMR (100 MHz, dmso-4) δ: 167.8, 156.4 (d, J=237 Hz), 152.2, 134.5, 134.4 (d, J=30 Hz), 133.5, 131.5, 130.6, 128.6 (d, J=9.4 Hz), 128.1 (d, J=3.6 Hz), 123.1, 118.2, 118.1, 114.9 (d, J=9.3 Hz), 112.9 (d, J=25 Hz), 80.0, 41.1, 33.2.

ES MS, m/z: 442 MH⁺, Cl₂ isotope pattern. Analytical purity: 99.9% (HPLC area % at 215 nm).

2R-7-(2,6-Dichlorophenyl)-5-fluoro-2,3-dihydro-2-aminomethylbenzofurane hydrochloride

The product of the preceding step, 2R-7-(2,6-Dichlorophenyl)-5-fluoro-2,3-dihydro-2-(N-phthalimidomethyl)benzofuran, (12.9 g, 29.2 mmol) was mixed with 70 mL of isopropanol and 15 mL of water. Hydrazine hydrate (55% hydrazine content, Aldrich, 5 mL, 90 mmol) was then added and the reaction mixture was magnetically stirred and heated at gentle reflux for 2 hr. (In case by-product phthalyl hydrazide crystallizes out and gets in a way of stirring it is re-dissolved by adding 3:1 mixture of isopropanol-water. It is very little soluble in isopropanol alone.) Dissolution of the staring material and formation of a clear solution was an indication that the reaction is done. It was confirmed by HPLC analysis before working up the reaction mixture.

To the hot solution was added 40 mL of 1 M aqueous NaOH and 100 mL of water. The product was extracted with MTBE (3×50 mL). Combined extracts were washed with 60 mL of 0.2 M aq. NaOH, then with water (2×50 mL) and finally with brine (50 mL). Resulting clear solution was dried over Na₂SO₄ for 1 hr, filtered through a paper filter and evaporated in vacuum to afford a light-yellow oil (it was slightly opalescent).

The oil was dissolved in 50 mL of EtOAc and to the solution was added rapidly 2 M solution of HCl in diethyl ether (Aldrich, 15 mL, 30 mmol). The salt precipitated rapidly (exothermic) and froze in a single chunk. It was broken up by shaking it with 100 mL of ether, then the slurry was stirred for 30 min in an ice bath. The salt was filtered, washed with 100 mL of ether, dried first on the filter in the stream of air until the filter reached room temp, and then overnight in a vacuum desiccator over CaSO₄.

Yield 9.4 g (92%) as white crystals. M.p. 231-233° C.

¹H NMR (400 MHz, dmso-d⁶) δ: 8.25 (broad s, 3H), 7.57 (m, J=8.1 Hz, 2H), 7.45 (dd, J=8.1 Hz, 1H), 7.24 (dd, J=2.6, 8.1 Hz, 1H), 6.90 (dd, J=2.6, 9.6 Hz, 111), 5.05 (d⁴, J=9.2, 7.9, 7.0, 4.5 Hz, H), 3.45 (dd, J=9.2, 16.6 Hz, 1H), 3.17 (dd, J=7.0, 16.6 Hz), 3.10 (dd, J=13.4, 4.5 Hz, 1H), 3.04 (dd, J=13.4, 7.9 Hz, 1H). Protons at 7.57 and 7.45 ppm form a second-order A₂B spin system with J_(AB)=8.1 Hz (determined by NMR simulation).

¹³C NMR (400 MHz, dmso-J₆) δ: 156.4 (d, J=257 Hz), 151.9, 134.5, 134.2, 133.5, 130.5, 128.7 (d, J=11 Hz), 128.2 (d, J=21 Hz), 118.3 (d, J=9 Hz), 115.0 (d, J=25 Hz), 112.9 (d, J=25 Hz), 80.0, 42.1, 32.8.

ES MS, m/z: 312 (M+H), Cl₂ isotope pattern.

Enantiomeric purity: 99.4% ee (chiral HPLC on Chiracel OD-H 0.46×25 cm, 1 mL/min 90% heptane/DIEA, 10% ethanol, area % at 280 nm).

Analytical purity: 99.8% (HPLC on Prodigy ODS3 0.46×15 cm, 1 mL/min water/TFA-MeCN/TFA 100 min gradient 0-100%, area % at 215 nm). Seventeen impurities in the range of 0.003-0.06 area % were detected totaling 0.19%.

For C₁₅H₁₃C₃FNO found C, 51.59%, H, 3.81%, N, 3.87%, anionic Cl 10.49%; calc'd C, 51.68%, H, 3.76%, N, 4.02%, anionic Cl 10.17%.

EXAMPLE 571 Determination of Binding Affinity and Agonist Activity of Compounds of Formula 1

The ability of the compounds of this invention to act as 5HT_(2C) agonists and partial agonists was established using several standard pharmacological test procedures; the procedures used and results obtained are provided below. In the test procedures, 5-HT stands for 5-hydroxytryptamine, mCPP stands for meta-chlorophenylpiperazine, and DOI stands for 1-(2,5-dimethoxy-4-iodophenyl)isopropylamine.

To evaluate the affinity of various compounds of Formula 1 for activity at the 5-HT_(2C) receptor, a CHO (Chinese Hamster Ovary) cell line transfected with the cDNA expressing the human 5-hydroxytryptamine-2C (h5-HT_(2C)) receptor was maintained in DMEM (Dulbecco's Modified Eagle Media) supplied with fetal calf serum, glutamine, and the markers: guaninephosphoribosyl transferase (GTP) and hypoxanthinethymidine (HT). The cells were allowed to grow to confluence in large culture dishes with intermediate changes of media and splitting. Upon reaching confluence, the cells were harvested by scraping. The harvested cells were suspended in half volume of fresh physiological phosphate buffered saline (PBS) solution and centrifuged at low speed (900×g). This operation was repeated once. The collected cells were then homogenized with a polytron at setting #7 for 15 sec in ten volumes of 50 mM Tris.HCl, pH 7.4 and 0.5 mM EDTA. The homogenate was centrifuged at 900×g for 15 min to remove nuclear particles and other cell debris. The pellet was discarded and the supernatant fluid recentrifuged at 40,000×g for 30 min. The resulting pellet was resuspended in a small volume of Tris.HCl buffer and the tissue protein content was determined in aliquots of 10-25 μL volumes. Bovine Serum Albumin (BSA) was used as the standard in the protein determination by the method of Lowry et al., (J. Biol. Chem., 193:265 (1951). The volume of the suspended cell membranes was adjusted with 50 mM Tris.HCl buffer containing: 0.1% ascorbic acid, 10 mM pargyline and 4 mM CaCl₂ to give a tissue protein concentration of 1-2 mg per ml of suspension. The preparation membrane suspension (many times concentrated) was aliquoted in 1 ml volumes and stored at −70 C until used in subsequent binding experiments.

Binding measurements were performed in a 96 well microtiter plate format, in a total volume of 200 μL. To each well was added: 60 μL of incubation buffer made in 50 mM Tris.HCl buffer, pH 7.4 and containing 4 mM CaCl₂; 20 μL of [¹²⁵I] DOI (S.A., 2200 Ci/mmol, NEN Life Science).

The dissociation constant, KD of [¹²⁵I] DOI at the human serotonin 5-HT_(2C) receptor was 0.4 nM by saturation binding with increasing concentrations of [¹²⁵I] DOI. The reaction was initiated by the final addition of 100 μL of tissue suspension containing 50 μg of receptor protein. Nonspecific binding is measured in the presence of 1 μM unlabeled DOI added in 20.0 μL volume. Test compounds were added in 20.0 μL. The mixture was incubated at room temperature for 60 min. The incubation was stopped by rapid filtration. The bound ligand-receptor complex was filtered off on a 96 well unifilter with a Packard® Filtermate 196 Harvester. The bound complex caught on the filter disk was dried in a vacuum oven heated to 60° C. and the radioactivity measured by liquid scintillation with 40 μL Microscint-20 scintillant in a Packard TopCount® equipped with six (6) photomultiplier detectors.

Specific binding is defined as the total radioactivity bound less the amount bound in the presence of 1 μM unlabeled DOI. Binding in the presence of varying concentrations of test drugs is expressed as percent of specific binding in the absence of drug. These results are then plotted as log % bound vs log concentration of test drug. Non linear regression analysis of data points yields both the IC₅₀ and the K_(i) values of test compounds with 95% confidence limits. Alternatively, a linear regression line of decline of data points is plotted, from which the IC₅₀ value can be read off the curve and the K_(i) value determined by solving the following equation:

$K_{i} = \frac{{IC}_{50}}{1 + {L/K_{D}}}$

where L is the concentration of the radioactive ligand used and the K_(D) is the dissociation constant of the ligand for the receptor, both expressed in nM.

The following K_(i)'s (95% confidence interval) are provided for various reference compounds:

Compound K_(i) Ritanserin 2.0 (1.3-3.1) nM Ketanserin 94.8 (70.7-127.0) nM   Mianserin 2.7 (1.9-3.8) nM Clozapine 23.2 (16.0-34.0) nM   Methiothepin 4.6 (4.0-6.0) nM Methysergide 6.3 (4.6-8.6) nM Loxapine 33.0 (24.0-47.0) nM   mCPP 6.5 (4.8-9.0) nM DOI 6.2 (4.9-8.0) nM

The ability of the compounds of Formula 1 to produce an agonist response at brain 5-HT_(2C) was assessed by determining their effect on calcium mobilization using the following procedure: CHO cells stably expressing the human 5-HT_(2C) receptor were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and non-essential amino acids. Cells were plated at a density of 40K cells/well in 96-well clear-bottom black-wall plates 24 hours prior to the evaluation of 5-HT_(2C) receptor-stimulated calcium mobilization. For calcium studies, cells were loaded with the calcium indicator dye Fluo-3-AM in Hank's buffered saline (HBS) for 60 minutes at 37° C. Cells were washed with HBS at room temperature and transferred to the fluorometric imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, Calif.) for acquisition of calcium images. Excitation at 488 nm was achieved with an Argon ion laser and a 510-560 nm emission filter was used. Fluorescence images and relative intensities were captured at 1 second intervals and cells were stimulated by addition of agonist after 10 baseline measurements using the internal fluidics module of the FLIPR. An increase in fluorescence counts corresponds to an increase in intracellular calcium.

For the evaluation of agonist pharmacology the calcium changes in response to different concentrations of agonist were determined using a maximum minus minimum calculation of the raw fluorescence count data. Calcium changes were then expressed as a percentage of the response observed with a maximally effective concentration of 5-HT. EC₅₀ values were estimated by non-linear regression analysis of the log-concentration % maximum 5-HT response curves using the 4-parameter logistic function. Preferred compounds are those with an EC₅₀ of ≦about 1000 nM, preferably ≦about 100 nM, more preferably ≦about 20 nM, still more preferably ≦about 5 nM, and most preferably ≦about 2 nM.

The following EC₅₀'s are provided for various reference compounds:

Compound EC₅₀ 5-HT 0.5 nM DOI 0.5 nM mCPP 5.4 nM

The results of the standard experimental test procedures described in the preceding paragraphs were as follows:

5-HT_(2C) Affinity 5-HT_(2C) Function Compound K_(i) (nM) EC₅₀ (nM) Emax (%) Example 1 43 926 90 Example 2 16 61 90 Example 3 204 Example 4 26 562 100 Example 5 9 208 90 Example 6 84 Example 7 160 Example 8 9 188 85 Example 9 10 194 85 Example 10 42 179 60 Example 11 106 Example 12 127 Example 13 133 Example 14 78 Example 15 222 Example 16 274 451 65 Example 17 66 100 70 Example 18 5 9.6 100 Example 19 2 66 100 Example 20 24 178 70 Example 21 9 86 85 Example 22 5 25 90 Example 23 9 73 80 Example 24 36 Example 25 18 10 90 Example 26 71 79 100 Example 27 39 2015 80 Example 28 16 77 90 Example 29 35 229 80 Example 30 191 Example 31 1372 Example 32 419 Example 33 32 Example 34 37 Example 35 141 Example 36 15 Example 37 1 1 100 Example 38 56 540 100 Example 39 43 Example 40 122 Example 41 25 Example 42 17 162 100 Example 43 100 748 80 Example 44 3 7 100 Example 45 2 5 90 Example 46 54 Example 47 0.4 5.4 100 Example 48 0.3 2.4 100 Example 49 10 132 80 Example 50 1 14 100 Example 51 1 Example 52 13 Example 53 1 45 80 Example 54 0.5 9 85 Example 55 3 48 70 Example 56 1 60 100 Example 57 1 12 80 Example 58 9 313 60 Example 59 2 127 100 Example 60 0.3 12 100 Example 61 37 1092 30 Example 62 40 130 70 Example 63 52 Example 64 13 70 100 Example 65 11 187 100 Example 66 5 250 100 Example 67 83 5763 70 Example 68 5 144 90 Example 69 96 Example 70 2 22 100 Example 71 1 1.4 100 Example 72 33 511 85 Example 73 5 41 100 Example 74 3 11 100 Example 75 103 Example 76 3 25 90 Example 77 2 8 100 Example 78 41 161 90 Example 79 2 24 95 Example 80 1 17 90 Example 81 24 294 50 Example 82 15 275 95 Example 83 1 7.9 100 Example 84 11 Example 85 5 557 100 Example 86 75 963 90 Example 87 0.8 20 90 Example 88 48 Example 89 40 Example 90 8 Example 91 5 45 100 Example 92 62 Example 93 13 874 80 Example 94 176 Example 95 1 65 100 Example 96 1 27 100 Example 97 4 577 60 Example 98 60 Example 99 21 838 60 Example 100 0.2 120 100 Example 101 0.2 0.32 100 Example 102 8 32 65 Example 103 7 996 80 Example 104 1 241 100 Example 105 1 4 95 Example 106 16 91 50 Example 107 1 93 100 Example 108 4 39 95 Example 109 25 3220 40 Example 110 9 1002 70 Example 111 26 Example 112 55 Example 113 130 Example 114 471 Example 115 79 Example 116 527 Example 117 263 Example 118 319 Example 119 78 Example 120 128 Example 121 44 681 60 Example 122 95 931 70 Example 123 207 Example 124 53 Example 125 276 Example 126 17 2715 40 Example 127 20 Example 128 41 24 70 Example 129 0.3 0.2 100 Example 130 4.8 54 80 Example 131 1.5 34 90 Example 132 20 1484 50 Example 133 3.6 66 80 Example 134 483 Example 135 131 Example 136 124 Example 137 1.2 473 90 Example 138 7.4 3802 60 Example 139 2.5 6 90 Example 140 0.3 0.72 90 Example 141 0.07 0.03 90 Example 142 1.6 101 80 Example 143 6.3 1 90 Example 144 6.1 4 90 Example 145 91 Example 146 2.4 5 90 Example 147 1.3 7 90 Example 148 12 290 70 Example 149 0.15 0.97 100 Example 150 4.1 74 100 Example 151 1.1 27 100 Example 152 6.6 202 70 Example 154 6.2 65 90 Example 155 9 43 90 Example 156 4.7 6 90 Example 157 58 Example 158 1.1 42 100 Example 159 12 636 80 Example 160 32 100 Example 161 8 32 90 Example 162 13 24 100 Example 163 0.23 2 90 Example 164 0.28 0.3 100 Example 165 18 80 70 Example 166 8 0.2 90 Example 167 3.1 21 90 Example 168 2 1 100 Example 169 14 50 100 Example 170 3.3 14 90 Example 171 0.88 0.7 100 Example 172 185 Example 173 326 Example 174 203 Example 175 384 Example 176 488 Example 177 353 Example 178 310 Example 179 435 Example 180 290 Example 181 146 Example 182 279 Example 183 178 Example 184 185 Example 185 159 Example 186 171 Example 187 247 Example 188 579 Example 189 363 Example 190 186 Example 191 270 Example 192 142 Example 193 246 Example 194 127 Example 195 0.48 9 80 Example 196 108 Example 197 63 Example 198 17 903 60 Example 199 19 416 80 Example 200 12 369 80 Example 201 8 396 80 Example 202 11 105 80 Example 203 8.5 187 80 Example 204 1.3 336 90 Example 205 3 280 80 Example 206 1.7 4 90 Example 207 128 112 80 Example 208 1.9 0.36 100 Example 209 2.3 57 90 Example 210 36 Example 211 19 672 70 Example 212 2.4 11 90 Example 213 9 100 Example 214 79 70 Example 215 5 80 80 Example 216 0.7 0.2 100 Example 217 0.4 143 70 Example 218 0.7 0.2 90 Example 219 7 79 90 Example 220 8 30 90 Example 221 1.4 2 90 Example 222 18 120 80 Example 223 10 30 80 Example 224 18 455 70 Example 225 1.2 3 90 Example 226 1.3 30 90 Example 227 1.5 3 95 Example 228 313 70 Example 229 0.4 6 100 Example 230 0.6 48 90 Example 231 0.4 80 Example 232 114 50 Example 233 614 20 Example 234 11 90 Example 235 49 50 Example 236 123 70 Example 237 0.57 3 80 Example 238 529 40 Example 239 1433 40 Example 240 89 70 Example 241 0.3 29 90 Example 242 3 48 90 Example 243 0.25 50 90 Example 244 0.74 52 90 Example 245 2 57 100 Example 246 23 1491 90 Example 247 15 164 90 Example 248 9 225 80 Example 249 4 21 90 Example 250 2.5 72 90 Example 251 0.38 8 90 Example 252 1.1 3 100 Example 253 8.6 251 90 Example 254 0.89 11 90 Example 255 5 79 90 Example 256 0.74 4 100 Example 257 28 194 80 Example 258 42 734 80 Example 259 69 Example 260 0.13 22 90 Example 261 0.5 67 90 Example 262 471 70 Example 263 1.8 0.8 100 Example 266 4.9 3 90 Example 267 730 80 Example 268 961 50 Example 269 5124 20 Example 271 594 90 Example 272 845 70 Example 274 330 70 Example 278 726 60 Example 279 155 70 Example 280 288 70 Example 281 3.8 35 90 Example 282 1.7 43 90 Example 283 1.2 6 100 Example 284 0.8 7 100 Example 286 0.76 6 100 Example 287 0.13 21 90 Example 288 7.1 38 100 Example 289 1 44 100 Example 290 1.7 58 80 Example 291 0.4 22 100 Example 292 4.9 66 100 Example 293 3.8 7 90 Example 294 0.11 8 90 Example 295 8 90 Example 296 50 80 Example 297 0.56 0.73 100 Example 298 11 30 90 Example 299 0.19 0.1 100 Example 300 0.1 3 90 Example 301 2 31 90 Example 302 0.3 2 100 Example 303 0.2 Example 304 1.7 Example 305 1.1 Example 306 0.58 0.64 100 Example 307 1 49 90 Example 308 0.9 24 90 Example 309 8 107 90 Example 310 13 137 90 Example 311 25 63 90 Example 312 15 25 90 Example 313 164 70 90 Example 314 18 42 90 Example 315 25 19 90 Example 316 64 Example 317 84 Example 318 98 Example 319 83 Example 320 107 Example 321 59 Example 322 427 Example 323 161 Example 324 60 Example 325 320 Example 326 34 228 80 Example 327 255 Example 328 61 Example 329 87 Example 330 88 Example 331 38 271 80 Example 332 37 111 80 Example 333 13 70 90 Example 334 324 Example 335 192 Example 336 45 123 90 Example 337 34 48 90 Example 338 14 44 90 Example 339 328 Example 340 88 Example 341 36 231 90 Example 342 28 590 80 Example 343 12 49 90 Example 344 275 2916 60 Example 345 98 Example 346 5000 Example 347 5000 Example 348 529 Example 349 760 Example 350 497 Example 351 87 Example 352 876 Example 353 845 Example 354 610 Example 355 385 Example 356 0.63 63 100 Example 357 18 2 100 Example 358 7 Example 359 10 8 90 Example 361 33 73 90 Example 362 36 343 70 Example 363 26 225 70 Example 364 0.9 62 85 Example 365 24 15 100 Example 366 13 394 80 Example 367 0.21 3 100 Example 368 1.4 4 90 Example 369 283 90 Example 370 30 190 80 Example 371 14 64 80 Example 372 23 224 80 Example 373 61 859 60 Example 374 0.6 19 100 Example 375 71 Example 376 88 Example 377 194 Example 378 201 Example 379 453 Example 380 424 Example 381 923 Example 382 801 Example 383 1758 Example 384 1255 Example 385 1354 Example 386 1025 Example 387 1549 Example 388 1580 Example 389 1620 Example 390 1.8 2 80 Example 391 0.2 80 Example 393 21.5 45 60 Example 395 0.3 0.4 90 Example 396 0.3 Example 397 1.6 Example 398 0.04 0.1 100 Example 400 0.5 Example 401 0.38 0.7 90 Example 402 0.24 0.1 90 Example 404 0.4 Example 406 0.51 9 100 Example 407 8.5 149 60 Example 408 0.46 6 90 Example 409 3 22 90 Example 410 0.08 0.05 90 Example 411 2.6 57 80 Example 412 5.3 34 90 Example 413 21 8 90 Example 414 3.4 781 60 Example 415 1.1 109 70 Example 416 1.6 467 70 Example 417 3.7 183 60 Example 418 1.1 59 80 Example 419 3.8 1359 80 Example 420 7.0 504 80 Example 421 1.5 93 70 Example 422 443 80 Example 423 6.1 28 70 Example 424 49 90 Example 425 9 100 Example 426 17 100 Example 427 298 80 Example 428 69 80 Example 429 2.8 16 92 Example 430 448 80 Example 431 63 90 Example 432 72 80 Example 433 3.5 1 100 Example 434 0.03 7 90 Example 435 82 80 Example 436 55 90 Example 437 30 80 Example 438 2.4 68 70 Example 439 0.45 6 90 Example 440 1.2 9 100 Example 441 10 531 70 Example 442 0.2 6 90 Example 443 4.8 5 90 Example 444 37 80 Example 445 0.48 1 90 Example 446 460 70 Example 447 3 90 Example 448 7 78 70 Example 449 1 2 90 Example 450 0.27 0.8 100 Example 451 0.31 137 80 Example 452 24 153 80 Example 453 24 80 Example 454 0.26 0.39 90 Example 456 4.1 50 100 Example 457 38 740 50 Example 458 17 212 80 Example 459 24 16 90 Example 460 215 90 Example 461 34 80 Example 462 79 80 Example 463 21 89 80 Example 464 462 70 Example 465 496 60 Example 466 55 70 Example 467 257 80 Example 468 73 80 Example 469 21 80 Example 470 289 70 Example 471 14 90 Example 472 353 80 Example 475 3.2 25 80 Example 476 0.2 5 100 Example 477 6.7 9 80 Example 478 11 225 70 Example 479 0.5 71 80 Example 480 4.4 251 70 Example 481 1.5 75 80 Example 482 7 143 80 Example 483 5 58 80 Example 484 0.51 43 70 Example 485 3 32 90 Example 486 0.2 5 90 Example 487 0.06 3 100 Example 488 0.34 132 90 Example 489 3 39 90 Example 490 1 6 100 Example 491 22 200 80 Example 492 3.1 7 80 Example 493 11 8 90 Example 494 35 475 60 Example 495 41 338 60 Example 496 46 510 60 Example 497 37 315 70 Example 498 35 326 70 Example 499 3.6 57 90 Example 500 86 256 80 Example 501 45 70 70 Example 502 60 Example 503 78 Example 504 1.2 27 90 Example 505 371 Example 506 1601 Example 507 2726 Example 508 1795 Example 509 5000 Example 510 5000 Example 511 248 Example 512 810 Example 513 1148 Example 514 242 Example 515 965 Example 516 1581 Example 517 2140 Example 518 40 384 80 Example 519 488 Example 520 372 Example 521 246 Example 522 474 Example 523 61 Example 524 136 Example 525 559 Example 526 25 50 90 Example 527 4744 Example 528 1093 Example 529 616 Example 530 915 Example 531 409 Example 532 3355 Example 533 1516 Example 534 1049 Example 535 1091 Example 536 1119 Example 537 1695 Example 538 380 Example 539 209 Example 540 486 Example 541 316 Example 542 372 Example 543 0.2 100 Example 544 73 70 Example 545 0.14 0.1 100 Example 546 2.3 Example 547 1.8 Example 548 2.3 Example 549 3.1 Example 550 0.37 0.4 100 Example 551 0.55 17 90 Example 552 0.3 Example 554 41 2 70 Example 555 0.6 4 80 Example 558 265 70 Example 559 0.3 7 90 Example 560 0.35 2 100 Example 561 2.7 21 80 Example 562 0.48 2 90 Example 563 135 70 Example 564 43 90 Example 565 287 70 Example 566 3 70 Example 567 9 60 Example 568 4 80 Example 569 6 60

The compounds of this invention thus have affinity for and agonist or partial agonist activity at brain serotonin 5HT_(2C) receptors. They are therefore of interest for the treatment of the central nervous system conditions described previously herein.

The entire disclosure of each patent, patent application, and publication cited or described in this document is hereby incorporated by reference. 

1-32. (canceled)
 33. A method for treating a patient suffering from schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, L-DOPA-induced psychosis, psychosis associated with Alzheimer's dementia, psychosis associated with Parkinson's disease, psychosis associated with Lewy body disease, dementia, memory deficit, or intellectual deficit disorder associated with Alzheimer's disease comprising administering to the patient a therapeutically effective amount of a compound of Formula 1:

or pharmaceutically acceptable salts thereof, wherein: R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring; alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen; R¹ and R² are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; R^(3a) and R^(3b) are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; R⁴, R⁵, R⁶, and R⁷ are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and n is 1, 2 or 3; wherein at least one of R⁴, R⁵, R⁶ and R⁷ is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R⁸, wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R⁸ is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms.
 34. The method of claim 33 wherein the patient is suffering from schizophrenia.
 35. A method for treating a patient suffering from bipolar disorders, depressive disorders, mood episodes, anxiety disorders, adjustment disorders, or eating disorders comprising comprising administering to the patient a therapeutically effective amount of a compound of Formula 1:

or pharmaceutically acceptable salts thereof, wherein: R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring; alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen; R¹ and R² are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; R^(3a) and R^(3b) are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; R⁴, R⁵, R⁶, and R⁷ are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and n is 1, 2 or 3; wherein at least one of R⁴, R⁵, R⁶ and R⁷ is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R⁸, wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R⁸ is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms.
 36. The method of claim 35 wherein the bipolar disorder is bipolar I disorder, bipolar II disorder, or cyclothymic disorder; the depressive disorder is major depressive disorder, dysthymic disorder, or substance-induced mood disorder; the mood episode is major depressive episode, manic episode, mixed episode, or hypomanic episode; the anxiety disorder is panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, or substance-induced anxiety disorder.
 37. The method of claim 36 wherein the condition is depressive disorder, bipolar disorder or mood episode.
 38. A method for treating a patient suffering from epilepsy, sleep disorders, migraines, sexual dysfunction, drug addiction, alcohol addiction, gastrointestinal disorders, or obesity comprising administering to the patient a therapeutically effective amount of a compound of Formula 1:

or pharmaceutically acceptable salts thereof, wherein: R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring; alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen; R^(3a) and R^(3b) are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; R⁴, R⁵, R⁶, and R⁷ are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and n is 1, 2 or 3; wherein at least one of R⁴, R⁵, R⁶ and R⁷ is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R⁸, wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R⁸ is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms.
 39. A method for treating a patient suffering from a central nervous system deficiency associated with trauma, stroke, or spinal cord injury comprising administering to the patient a therapeutically effective amount of a compound of Formula 1:

or pharmaceutically acceptable salts thereof, wherein: R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring; alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen; R¹ and R² are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; R^(3a) and R^(3b) are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; R⁴, R⁵, R⁶, and R⁷ are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and n is 1, 2 or 3; wherein at least one of R⁴, R⁵, R⁶ and R⁷ is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R⁸, wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R⁸ is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms.
 40. A composition comprising a compound of Formula 1:

or pharmaceutically acceptable salts thereof, wherein: R and R′ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring; alternatively R and R′ can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen; R¹ and R² are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; R^(3a) and R^(3b) are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; R⁴, R⁵, R⁶, and R⁷ are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and n is 1, 2 or 3; wherein at least one of R⁴, R⁵, R⁶ and R⁷ is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or —Y—R⁸, wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R⁸ is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms; and one or more pharmaceutically acceptable carriers. 